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UNIVERSIDAD DE LA LAGUNA

INSTITUTO UNIVERSITARIO DE

BIO-ORGÁNICA "ANTONIO GONZÁLEZ" (IUBO-AG)

MEMORIA DE ACTIVIDADES 2015

Colabora en la Financiación el Cabildo Insular de Tenerife

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ÍNDICE

Página 1. Fines y Objetivos 3 2. Equipo Directivo 5 3. Comisión Permanente 5 4. Personal Investigador 6 5. Personal en Formación 7 6. Personal de Administración y Servicios 8 7. Investigadores, Profesores Invitados 9 8. Estancia de Investigadores en otros centros 11 9. Reconocimiento científico y Jubilaciones 12

MEMORIA CIENTÍFICA

10. Proyectos de Investigación 14 11. Publicaciones 39 12. Participaciones en Congresos 92 13. Tesis Doctorales Defendidas en 2015 139 14. Premios y Reconocimiento 142 15. Programas de posgrados, másteres, títulos propios y programas de

doctorado impartidos, organizados o promovidos por el instituto 144

16. Organización de Conferencias, Congresos, Seminarios y Jornadas de Divulgación

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17. Conferencias y Cursos impartidos 148 18. Convenios de Colaboración 150 19. Trabajo Fin de Grado y Trabajos Fin de Máster realizados en el IUBO 153 20. Otras Actividades 155 21. Resumen Estadístico 158

MEMORIA ECONÓMICA

22. Subvención del Cabildo Insular de Tenerife 160 23. Subvención de la Universidad de La Laguna 161

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1. FINES Y OBJETIVOS

El Instituto Universitario de Bio-Orgánica Antonio González (IUBO-AG) es un centro

multidisciplinar orientado a la investigación en el campo de la Química Bio-Orgánica, Productos Naturales Bioactivos y Química Médica. El Instituto fue fundado en los años 60 con la necesidad de estudiar los metabolitos secundarios producidos por organismos marinos y terrestres, para proporcionar una nueva fuente de compuestos únicos. Actualmente, los objetivos del Instituto son el aislamiento, la biosíntesis, los cultivos de microorganismos, la biotecnología y la síntesis total de sustancias farmacológicamente activas procedentes de fuentes naturales. Además, son áreas de investigación de interés actual la evaluación biológica, el aislamiento y producción de toxinas, estudios NMR de procesos biológicos, insecticidas y repelentes naturales, etc.

Líneas de investigación IUBO-AG Agentes anticancerígenos procedentes de fuentes naturales

Varios productos naturales y sus derivados semisintéticos son producidos dentro de varios proyectos comunes para el desarrollo de antitumorales con nuevos mecanismos de acción. Algunos productos recientemente han mostrado in vitro una reversión de la MDR (multirresistencia a fármacos) y efectos quimiopreventivos sobre el virus de Epstein-Barr.

Estudios de la relación Estructura-Actividad

Para entender la base estructural de la actividad biológica de una molécula y para dirigir el diseño de un fármaco más potente, el modelo cuantitativo tridimensional de la relación estructura-actividad (3D-QSAR) se realiza a partir de quimiotecas de compuestos relacionados.

Agentes antimicrobianos procedentes de fuentes naturales

Productos naturales procedentes de plantas y de derivados semisintéticos son de interés para luchar contra varios microorganismos y sus mecanismos de acción.

NMR en el estudio de procesos biológicos

Técnicas avanzadas de Resonancia Magnética Nuclear (NMR) se aplican para determinar interacciones enzima-inhibidor como una alternativa novedosa en la búsqueda de nuevos fármacos.

Organismos marinos y toxinas

Los dinoflagelados son organismos marinos responsables de las mareas rojas y el envenenamiento de moluscos. Entre otras, el ácido okadaico y las yessotoxinas son las toxinas más comunes presentes en crustáceos europeos. Desarrollamos sistemas de cultivos para proveernos de suficientes cantidades de toxinas para realizar estudios biológicos.

Insecticidas y repelentes

Se están aislando productos naturales para su uso contra plagas, especialmente las que afectan a la agricultura. Estos proyectos se llevan a cabo en colaboración con instituciones públicas y compañías agroquímicas de Europa y de América Latina.

Productos químicos y farmaquímicos

Nuestro instituto cuenta con una larga experiencia en el campo de la síntesis orgánica destinada a la síntesis de sustancias medicinales, especialmente enfocada en procesos

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asimétricos. Es de interés particular encontrar el desarrollo de nuevas metodologías para la síntesis total de sustancias activas biológicamente como toxinas, aminoácidos, análogos de la esfingosina, alcaloides, etc.

Catálisis metálica sostenible

En el actual contexto socioeconómico, el concepto de sostenibilidad ha irrumpido con mucha fuerza. Para el ser humano, la sostenibilidad consiste en satisfacer las necesidades de la actual generación sin sacrificar la capacidad de futuras generaciones. Dicho concepto tiene implicaciones medioambientales, económicas y sociales.

Actualmente se consumen muchos recursos, se encarecen los precios, mientras la sociedad demanda procesos más respetuosos con el medio ambiente.La catálisis posee el potencial para convertirse en una de las claves tecnológicas del siglo XXI. Así se podrán llevar a cabo nuevas reacciones y se desarrollarán procesos que permitan un ahorro de energía. Se podrán desarrollar nuevas metodologías sintéticas que tengan el menor impacto medioabmiental. Sin embargo muchos de los catalizadores empleados hoy en día son metales de transición caros, poco abundantes en cantidades que garanticen un total suministro en épocas venideras. Dentro de este contexto, estamos interesados en el desarrollo de nuevas metodologías sintéticas orientadas a la obtención de heterociclos (oxigenados y nitrogenados) de diversos tamaños, con potencial actividad biológica. Aplicar dicha metodología en la síntesis de productos naturales bioactivos y derivados utilizando una catálisis metálica sostenible. Por todas estas razones el hierro es una excelente alternativa a los metales preciosos en catálisis. Es uno de los metales más abundantes, es accesible, con bajo precio y respetuoso con el medio ambiente. Varias sales de hierro y complejos de hierro son accesibles comercialmente a gran escala o fáciles de sintetizar. Es importante destacar que el hierro forma parte de sistemas biológico como elemento esencial. El incremento en el número de reacciones catalizadas por hierro que se han publicado reflejan una mayor demanda de la química sostenible.

Descubrimiento fenotípico de compuestos antiproliferativos

Nuestra aproximación se fundamenta en el uso de estrategias convergentes para la identificación precoz de la diana terapéutica de cada molécula bioactiva mediante la aplicación de una estrategia global. Los compuestos que se analizan provienen no solo de grupos de investigación de la Universidad de La Laguna, sino de colaboraciones estables que mantenemos con grupos químicos nacionales e internacionales.

Farmacología e investigaciónes biomédicas

El IUBO-AG participa activamente en programas de investigación en colaboración con los hospitales y centros de investigación biomédicos de Canarias. El resultado de esta iniciativa es la constitución del CIBICAN (Centro de Investigaciónes Biomédicas de Canarias) diseñado hacia el desarrollo en conjunto en los distintos aspectos de las Ciencias Biomédicas y de la Salud en Tenerife y Canarias.

Micromorfología y biomarcadores arqueológicos Al igual que hoy en día, la actividad humana en el pasado se desarrollaba en torno a materiales orgánicos (comida, vestimenta, el paisaje natural...etc.). A pesar de ello, el registro arqueológico orgánico es desconocido en su mayor parte debido a su bajo potencial de conservación. Nuestra línea de investigación se basa en el análisis microscópico y molecular de sedimento arqueológico para la identificación de partículas orgánicas y biomarcadores que nos permitan generar una visión más completa del pasado humano.

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2. EQUIPO DIRECTIVO

Director: Dr. D. Manuel Norte Martín Categoría: Catedrático Email: mnorte@ull.es

Subdirector: Dr. D. José Javier Fernández Castro Categoría: Profesor Titular Email: jjfercas@ull.es

Secretaria: Dra. Dña. Ana Estévez Braun Categoría: Profesora Titular Email: aestebra@ull.es

3. COMISIÓN PERMANENTE

Director: Dr. D. Manuel Norte Martín Categoría: Catedrático Email: mnorte@ull.es

Subdirector: Dr. D. José Javier Fernández Castro Categoría: Profesor Titular Email: jjfercas@ull.es

Secretaria: Dra. Dña. Ana Estévez Braun Categoría: Profesora Titular Email: aestebra@ull.es

Vocal: Dr. D. Víctor S. Martín García Categoría: Catedrático Email: vsmartin@ull.es

Vocal: Dr. D. Jesús María Trujillo Vázquez Categoría: Catedrático Email: jtruvaz@ull.es

Vocal: Dra. Dña. Isabel López Bazzocchi Categoría: Profesor Titular Email: ilopez@ull.es

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4. PERSONAL INVESTIGADOR

CU: Catedrático Universidad; TU: Profesor Titular Universidad; PCD: Profesor Contratado Doctor

Nombre y apellidos Categoría Correo electrónico

Ana Estévez Braun TU aestebraull.es

Ana Raquel Díaz Marrero Investigador IMBRAIN adiazmar@ull.es

Antonio M. Hernández Daranas Investigador IMBRAIN adaranas@ull.es

Carolina Mallol Duque Investigadora Ramón y Cajal cmallol@ull.es

Celina Elena García González PCD Tipo 1 cgargon@ull.es

Fernando Pinacho Crisóstomo Investigador IMBRAIN fpinacho@ull.es

Ignacio Antonio Jiménez Díaz TU ignadiaz@ull.es

Isabel López Bazzocchi TU ilopez@ull.es

Jesús Manuel González Díaz TU jglezdll.es

Jesús María Trujillo Vázquez CU jtruvaz@ull.es

José Adrián Gavín Sazatornil CU jgavin@ull.es

José Antonio Palenzuela López CU jpalenz@ull.es

José Javier Fernández Castro TU jjfercas@ull.es

José Manuel Padrón Carrillo PCD Tipo 1 jmpadron@ull.es

Juan Ignacio Padrón Peña Científico titular CSIC jipadron@ull.es

Manuel Norte Martín CU mnorte@ull.es

Mª del Mar Afonso Rodríguez TU mmafonso@ull.es

Mª Josefina Rodríguez Enríquez TU jenrique@ull.es

Mª Luisa Souto Súarez PCD Tipo 1 msouto@ull.es

Matías López Rodríguez TU malopez@ull.es

Miguel Ángel Ramírez Muñoz TU mramirez@ull.es

Miguel Xavier Jesús Josefat Fernandes

Investigador IMBRAIN mfernand@ull.edu.es

Oliver Callies Investigador IMBRAIN oliver.callies@arcormail.de

Ricardo Borges Jurado CU rborges@ull.es

Ricardo Guillermo Álvarez TU riguial@ull.es

Rita Hernández Molina TU rrhernan@ull.es

Romen Carrillo Fumero Investigador IMBRAIN rocarril@ull.es

Tomás Martín Ruíz Científico titular CSIC tmartin@ipna.cisic.es

Víctor S. Martín García CU vmartin@ull.es

Antonio V. Herrera Herrera Investigador Proyecto ERC avherrer@ull.edu.es

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5. PERSONAL EN FORMACIÓN

Nombre y apellidos Categoría Correo electrónico Adrian José Santiago Benítez

Alumno de Doctorado Ajsb_88@hotmail.com

Adrián Morales Amador Alumno de Doctorado adrian_tf@hotmail.com Alberto Jonatan Martín Rodríguez

Becario Predoctoral PLOCAN martin.rodriguez.aj@gmail.com

Alberto Kevin Muro Lorenzo Trabajo Final de Máster Alejandro Gutiérrez González

Prácticas de verano, estudiante de química

Ángel Amesty Arrieta Farmacéutico. Becario Universidad de Caracas

angelamesty@yahoo.es

Boukerouis Djoudi Univ. Laghouat, Algeria boukerourousdjoudi@yahoo.fr Caterina Rodríguez de Vera Alumna de Doctorado Caterina_rv@hotmail.com Claudia Rodríguez Sánchez Trabajo Fin de Grado alu0100767384@ull.edu.es

Dácil Reyes González Estudiante CFGM Marítimo Pesquera – Cultivos Acuícolas

Diego Manuel Monzón Rodríguez

Alumno de doctorado alu0100542936@ull.edu.es

Eduardo Iván De la Guardia Salazar de Frias

Trabajo Fin de Grado alu0100606614@ull.edu.es

Eduardo Martínez Rojas Estudiante CFGS Informática y Comunicaciones

Elva Martín Batista Trabajo Fin de Grado Gabriela Brieba Plata Personal Adscrito g.b.plata@gmail.com Guillermo Díaz Crespín Becario MAE gdiazcrespin09@gmail.com Héctor Arzola Hernández Estudiante Grado Química ektor202@hotmail.com Héctor José Tejera Linares Estudiante CFGM Marítimo

Pesquera – Cultivos Acuícolas

Humberto José Domínguez Rodríguez

Becario FPU humbertodguez@gmail.com

Iris Pérez García-Calvo Trabajo Fin de Grado Jasmina González Trabajo Fin de Grado Jose Gerardo Hernández Jiménez (Dr.)

Contratado CONSOLIDER jghdezj@gmail.com

Julio Rodríguez López Becario FPI - Doctorando jrlopez@ull.es Kriss Dayana Pantoja Universidad del Valle

Colombia

Lorena Cruz García Trabajo Fin de Grado Lorenacg7@hotmail.com Marcelle Dayana Peretti Martín

Alumna de Doctorado mdperretti@gmail.com

María Fariña Ramos Estudiante de Máster, ULL Del 3/11/14 previsto fin del Máster

María Ainara Sistiaga Gutiérrez

Contrato Proy. del Consejo Europeo de Investigación (ERC)

msistiag@ull.es

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6. PERSONAL DE ADMINISTRACIÓN Y SERVICIOS

Nombre Categoría

Ángel López Ruiz Grupo IV

Antonio Díaz Herrera Grupo III

Gregorio Rois Grajal Grupo IV

Nicolás Pérez Pérez Grupo C

Pastora Izquierdo Herrera Grupo III

Pedro Rodríguez Zuppo Grupo III

Yo no pondría a Pedro

Miguel Díaz Amador Trabajo Fin de Grado Mónica Blanco Freijo Estudiante de Doctorado Nathalia Peixoto Nocchi Carneiro

Becaria Ciencia sin Fronteras nathaliapeixop@hotmail.com

Nayra Inmaculada Rodríguez Perestelo

Contratada Proyecto nirperes@ull.es

Neldemary Arismendi Díaz Estudiante Fin de Grado Oliver Callies Universidad Albert-Ludwigs

de Freiburg oliver.callies@arcormail.de

Pedro Martín Acosta Alumno de Doctorado pmartac@gmail.com Priscila López Rojas Alumna de Doctorado alu0100595659@ull.edu.es Raquel Pérez Acosta Trabajo Fin de Grado Rayco Herbert Pérez Schmeller

Trabajo Fin de Grado

Rodolfo Gastón Silveira Dorta (Dr.)

Becario Predoctoral ACIISI Baja el 25/09/2015

gastonsilveira@gmail.com

Rosalía González Brito Alumna de Doctorado Sandra María Oramas Royo (Dra.)

Licenciada en Químicas. Becaria Gobierno Autónomo

soramasroyo@gmail.com

Sara Tejera Díaz Estudiante postgrado stejera@ull.es Sergio Joaquín Álvarez Méndez

Becario FPU - Doctorando salvmen@ull.es

Sixto José Pérez Moreno Becario FPU - Doctorando sjperez@ull.es Varkha Rammnani Gul Trabajo Fin de Grado

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7. INVESTIGADORES Y PROFESORES INVITADOS

Nombre Procedencia Periodo de Estancia Ahmed Makhlouci (Dr.) Univ. Bechar, Algeria Del 7/05/15 al 13/05/15 Aline Zancheti Ameni Univ. de Sao Paulo Del 16/10/14 al 13/03/2015 Ana Maria Loureiro da Seca Universidad de Azores Del 8/06/15 al 12/06/15 Azzurra Jon Erasmus Del 11/02/15 al 31/07/15 Cintia Anabella Menéndez Estudiante Doctorado Univ.

Nacional del Sur, Argentina Del 6/9/15 al 4/12/15

Elena Alicia Cóndor Cuyubamba

Prof. Univ. Nacional de Ingeniería, Perú

Del 1/10/15, previsto hasta final febrero 2016

Ines Sifaoui La Maisa, Túnez Del 01/10/15 al 20/12/15 Irene Lagunes Apodaca Universidad Veracruzana,

México. Becaria CONACYT Del 15/02/15 al 15/08/15

Jimena Scoccia (Dra.) Ayudante Docencia, Univ. Nacional del Sur, Argentina

Del 14/09/15 al 13/12/15

Dr. Francisco Cen Pacheco Universidad de Veracruz Del 01/06/15 al 01/08/15 Dr. José David Terrero Univ. Autónoma de Santo

Domingo Del 9/07/15 al 17/07/15

Dr. Larbi Ben Larbi Univ. Bechar, Algeria Del 26/02/15 al 25/05/15 Lina Graciela Quispe Quispe Univ. Nac. San Agustín de

Arequipa Del 21/01/15 al 07/03/15

Marco Bassetto Univ. de Studi di Padona. Becario Erasmus

Del 03/02/15 al 22/09/15

Dr. Marvin José Núñez Rivas F. Farmacia, Univ. de El Salvador

Del 12/09/15 al 22/10/15

Pabla Andrea Barra Oliva Univ. de Concepción, Chile Del 7/05/15 al 4/08/15 Salma Saoudi Laboratoire d’Ecologie et de

Technologie Microbiennes”, Letmi-INSAT, University of Carthage, Tunisia

Del 29/09/2015 al 20/12/2015

Soumaya Hajaji Faculty of Sciences of Bizerte, University of Carthage, Tunisia

Del 20/09/15 al 20/12/15

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8. ESTANCIAS DE INVESTIGACIÓN EN OTROS CENTROS Investigador: Antonio Manuel Hernández Daranas. Lugar: Imperial College London Grupo: Dr. John C. Lindon Fechas: Julio-Agosto 2015 Investigador: Alberto Jonathan Martín Rodríguez. Lugar: Instituto Karoliska (Suecia) Grupo: Ute Rouling Fechas: Febrero-Abril 2015 Investigador:. María Josefina Rodríguez Enríquez Lugar: Plant Sciences Department University of Oxford UK Fechas: 20 de Junio del 2015 al 26 de Enero de 2016

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9. RECONOCIMIENTO CIENTÍFICO Y JUBILACIONES

El día 18 de diciembre se celebró en el Salón de Actos del IUBO el acto de reconocimiento a los Dres D. Matias López Rodríguez y D. Javier Gutiérrez Luis por la labor investigadora que desarrollaron en el IUBO. En el mismo acto, se reconoció igualmente las labores de apoyo a la investigación realizada por Doña Pastora Izquierdo Herrera. En dicho acto el Director del Instituto Dr. Manuel Norte puso de manifiesto la trayectoria y los resultados mas relevantes alcanzados por los investigadores, así como su aportación al crecimiento del Instituto a lo largo, en ambos casos, de mas de cuarenta años de dedicación al mismo. Así mismo se puso de manifiesto la crucial labor de apoyo a la investigación de Doña Pastora Izquierdo en las diferentes funciones que realizó durante sus años en activo. A los Dres López Rodríguez y Gutiérrez Luis se les entregó la medalla del IUBO y Doña Pastora Izquierdo una Placa conmemorativa.

Una vez finalizado el acto, se ofreció a todo el personal del IUBO y resto de asistentes, un brindis en las dependencias del Instituto.

Pastora Izquierdo (2ª Izda); Dr. Javier Gutiérrez (3º Izda) y Dr Matias López (2ºdcha) junto con el equipo directivo del IUBO

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MEMORIA CIENTÍFICA

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10. PROYECTOS DE INVESTIGACIÓN SUBVENCIONADOS

Síntesis de nuevas entidades químicas para cartografiar la bioactividad en el espacio químico Resumen Nuestra propuesta de investigación se centra en la síntesis de pequeñas moléculas para cartografiar la bioactividad en el espacio químico. El objetivo general del proyecto es diseñar y desarrollar metodologías sintéticas basadas en procesos catalíticos (orgánicos y metálicos) y/o dominó para la síntesis de colecciones moleculares de moléculas pequeñas, las cuales incluirán productos naturales y homólogos, motivos estructurales privilegiados y plataformas moleculares sintéticas. Haremos uso de estrategias sintéticas tales como síntesis orientada a una estructura (producto natural) (TOS), síntesis de estructuras homólogas a partir de intermedios avanzados comunes (DTS) y síntesis orientada a la diversidad como ejes de innovación para la construcción molecular y el descubrimiento de nuevos cabezas de serie. Las colecciones de pequeñas moléculas serán evaluadas de acuerdo a nuestra implementación de la aproximación denominada “Phenotypic Drug Discovery” (descubrimiento de fármacos basados en fenotipos), la cual permite explorar contextos de relevancia biológica sin conjeturar mecanismos de acción. Los módulos existentes de evaluación contribuirán a explorar áreas relevantes del espacio farmacológico (biológico) (antitumorales, antibióticos, anti-infamatorios), en busca de nuevas topologías químicas bioactivas. Utilizaremos los tres módulos de ensayos fenotípicos denominados Cáncer, Enfermedades Infecciosas y Lesión Pulmonar Aguda. Los cabezas de serie seleccionados en los ensayos primarios serán validados mediante ensayos secundarios y de confirmación para descubrir sus mecanismos de acción y así como la identificación de la diana biológica. En el contexto de este proyecto desarrollaremos un nuevo módulo de evaluación destinado al estudio de la actividad “antibiofouling” (el biofouling es la acumulación no deseada de depósitos, esencialmente microbiológicos, sobre una superficie artificial sumergida o en contacto con agua de mar). Synthesis of Novel Chemical Entities to Map Bioactivity In The Chemical Space Synocemabics Summary This research proposal relates to the synthesis of small molecules to map bioactivity in the chemical space. The general aim of the project is to design and develop synthetic methodologies based on domino and/or catalytic manifolds (organic and metallic) for the synthesis of libraries of small molecules including natural products, natural products-like,

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privileged structural motives and synthetic scaffolds. We will make use of front edge synthetic strategies such as target-oriented synthesis, diverted–oriented synthesis and diversity-oriented synthesis as innovation axes for molecular construction and lead discovery. The resulting small molecule libraries will be screened using our implementation of the so-called Phenotypic Drug Discovery approach, which allows interrogating relevant biological contexts without predisposed bias toward action mechanisms. Running screening modules will contribute to explore relevant areas of the pharmacological (biological) space (antitumor, antibiotics, anti-inflammatory) in the search for novel bioactive chemical topologies. Three phenotypic assay modules, namely Cancer, Infectious Diseases and Acute Lung Injury will be used. Primary assays will be used to select initial lead compounds that will be submitted to secondary and confirmatory assays to unravel their mechanism of action in addition to identification of the biological target. Within this project we will start a new module devoted to the evaluation of antibiofouling activity Número de investigadores/as: 6 Cód. según financiadora: CTQ2011-28417-C02-01 Fecha de inicio: 01/01/2012 , 3 años Fecha fin: 31/12/2015 Entidades participantes: Consejo Superior de Investigaciones Científicas; IUBO- AGUniversidad de La Laguna Cuantía subproyecto: 216.590 € IP: Dr. D. Victor Sotero Martín García

Síntesis orgánica bajo el paradigma de la sostenibilidad Resumen El concepto de sostenibilidad en química ha emergido como uno de los retos más significativos y paradigmáticos a los que se enfrenta la comunidad química en este siglo. Este nuevo paradigma requiere una nueva aproximación holística a la síntesis orgánica. El objetivo de sintetizar cualquier molécula imaginable a partir de precursores simples y accesibles, faro de guía de la síntesis orgánica durante el siglo pasado, ha dejado su lugar a uno nuevo y mucho más ambicioso: la síntesis de estas moléculas en una manera realmente práctica (aplicable), cualquiera que sea su forma, tamaño o complejidad. Este nuevo cambio exige que los procesos no sólo sean eficientes y selectivos (valores intrínsecos del proceso), sino que además, sean respetuosos con el medio ambiente, simples de ejecutar, escalables y que además, se desarrollen de acuerdo a los principios de la economía instaurados en la síntesis orgánica actual (átomo, etapas, ajustes redox)(valores extrínsecos del proceso). El proyecto que presentamos está dirigido a desarrollar procesos catalíticos y/o dominó capaces de ser

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implementados en metodologías sintéticas que cumplan estos principios. Estas metodologías las aplicaremos a la construcción eficiente de quimiotecas (librerías) de moléculas pequeñas que incorporen productos naturales y homólogos, nuevos quimiotipos moleculares, motivos estructurales privilegiados y estructuras moleculares basadas en modelos naturales. Serán diseñadas para ser escalables, químicamente sostenibles y compatibles con los requerimientos metodológicos de los programas de construcción molecular basados en la síntesis total o en la síntesis orientada a la diversidad estructural. En conjunto, este proyecto esta soportado sobre tres ejes de innovación: síntesis orgánica, catálisis química y control de la reactividad química, y utiliza la química, la farmacología, la biomedicina y la ciencia de los materiales como vehículos de innovación. Los principales retos que asumimos en este proyecto se resumen en: 1) el diseño de nuevos procesos catalíticos y/o dominó basado en la catálisis metálica sostenible (hierro entre otros metales) y organocatálisis; 2) la implementación de procesos organocatalíticos basados en interacciones no covalentes y compatibles con la presencia de agua; y 3) el desarrollo de programas de construcción molecular sostenibles y basados en la síntesis total (TS), en la síntesis total diversificada (DTS) y en la síntesis orientada a la diversidad (DOS) como herramientas para la navegación y exploración del espacio químico en la búsqueda de nuevas anotaciones biológicas (farmacológicas). Organic synthesis under the sustainability paradigm approach Summary Sustainable chemistry has emerged as one of the most significant and paradigmatic challenges that the chemical community will be facing in the coming years. This new paradigm requires a new holistic approach to organic synthesis. The old aim to synthesize any imaginable molecule from simple and accessible precursors has changed to a new and more ambitious challenge: the synthesis of molecules in a truly practical way, whatever the molecular complexity, shape and size. Therefore, this new challenge requires chemical processes not only to be efficient, selective and high yielding (intrinsic reaction values) but also environmentally friendly, instrumentally simple, scalable and accomplishable with atom, step, and redox economy (extrinsic reaction values). The project that we present herein is aimed to develop catalytic and/or domino processes amenable to be implemented in synthetic methodologies according to this new paradigm. These methodologies will be applied to the efficient construction of small molecule libraries comprising natural products and homologues, new chemotypes, privileged scaffolds and new natural product-like scaffolds. They will be designed to be scalable, sustainable and compatible with total diverted synthesis and diversity-oriented synthesis programs. Overall, the current project is based on three innovation axes: organic synthesis, catalysis and chemical reactivity, and uses chemistry, pharmacology, biomedicine and materials as innovation vehicles. The main challenges pursued in this project are summarized: 1) The design of new and practical catalytic and/or domino reactions based on sustainable metal catalysts (iron among others) and/or organocatalysis; 2) the implementation of water-compatible non-covalent organocatalytic processes, and 3) the development of sustainable molecular construction programs based on total synthesis (TS), target oriented synthesis (TOS), diverted total synthesis (DTS) and diversity-oriented synthesis (DOS) for the navigation and exploration of the chemical space in the search of new biological (pharmacological) annotations and lead (probe) discovery Número de investigadores/as: 6 Cód. según financiadora: CTQ2014-56362-C2-1-P

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Fecha de inicio: 01/01/2015, 4 años Fecha fin: 31/12/2018 Entidades participantes: IUBO- AG, Universidad de La Laguna Cuantía subproyecto: 257.730 € IP: Dr. D. Victor Sotero Martín García

Compuestos Bioactivos de Organismos Marinos: estudios estructurales, farmacológicos y biotecnológicos Resumen Las microalgas marinas juegan un papel crucial en los ecosistemas debido a su actividad fotosintética y de entre ellas, nuestro proyecto se interesa por el grupo de los dinoflagelados capaces de originar afloramientos o “blooms” conocidos como “mareas rojas”. Éstas se clasifican habitualmente en función de los efectos toxicológicos en humanos. Por otro lado, los dinoflagelados marinos podrían llegar a ser auténticas “factorías celulares” de importantes sustancias bioactivas con diferentes aplicaciones farmacológicas. Estudiaremos a gran escala especies de Prorocentrum orientados a los metabolitos más polares, apoyándonos en los hallazgos en el IUBO de Belizeanolido y Ácido Belizeanóico, dos ejemplos de los denominados “SuperCarbonChain Ccompounds, SCC)” y otros ejemplos de lactonas macrocíclicas. Dado el interés de estos dinoflagelados como productores, en la UAL se propone establecer las condiciones para su cultivo semi-industrial y productivo. El objetivo es adaptar y poner a punto fotobiorreactores de decenas de litros trabajando el escalado para la máxima producción de toxinas y de biomasa en el cultivo externo para los dinoflagelados seleccionados. Moléculas de esta complejidad generan nuevos problemas que han de resolverse. En este sentido se está desarrollando una metodología por RMN directa y simple para establecer la configuración de los centros quirales en sistemas de anillos de cinco miembros muy comunes en este tipo de estructuras y de establecer el origen biosintético de estas estructuras. El interés de estas sustancias también radica en su potente actividad inhibitoria de proteínas fosfatasas, y hoy en día sigue suponiendo un gran reto la búsqueda de nuevos inhibidores selectivos. En el IUBO se realizarán estudios de inhibición in vitro; estudios estructurales y conformacionales del AO y análogos; cálculos teóricos de docking para determinar su modo de unión a los enzimas y establecer los requisitos estructurales necesarios para la inhibición selectiva de PP1 y PP2A. Los datos de inhibición in vitro serán contrastados en la UO con los de cultivos de cerebelo, para identificar los motivos estructurales asociados a la efectividad inhibidora en células vivas, la cual, dada la gran complejidad estructural de las PPs y su regulación, puede diferir significativamente de la actividad in vitro. Se estudian también otros poliéteres de algas rojas del género Laurencia para información de moléculas y motivos estructurales más simples con

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actividad inhibitoria. En la UAL, se estudian sus interacciones con células inmunitarias, evaluando la toxicidad y la función biológica de estas células ante la toxina o bioproducto. En el caso de linfocitos T, su capacidad para reconocer inmunógenos. Dada la gran sensibilidad del SNC a la acción a largo plazo de estos compuestos usaremos cultivos celulares primarios y organotípicos de SNC. Las propiedades eléctricas neuronales permiten aproximaciones únicas de determinación de efectos fisiológicos subtóxicos como los registros extracelulares con matrices de microeléctrodos. El estudio de las vías bioquímicas estará orientado especialmente a la identificación de mecanismos neuroprotectores. Finalmente en este proyecto nos planteamos iniciar el estudio a pequeña escala de 50 especies de diferentes géneros de dinoflagelados de la colección del IEO (Vigo) para estudiar su bioactividad y elegir los adecuados para proseguir su escalado y futuros estudios Bioactive Molecules From Marine Organisms: Structural, Pharmacological And Biotechnological Studies Summary Among marine organisms, microalgae play a crucial role in ecosystems due to their photosynthetic activity. This group is characterized by their ability to produce blooms known as "red tides” and classified according to the toxicological effects provoked in humans. There is no doubt that marine dinoflagellates could become real "cell factories" of important bioactive substances with different biotechnological applications. Thus, on the basis of the results recently obtained from of P. belizeanum, in this project we propose to continue the development of large-scale cultures of Prorocentrum species focussed on the search of highly polar metabolites. Certainly, we have isolated and characterized two new examples of the so-called "SuperCarbonChain compounds,SCC)" named belizeanoic acid and belizeanolide. Furthermore we have detected similar metabolites that are still under study. In addition, we propose to undertake in the UAL further studies to find the optimal the conditions to produce massive cultures. The ultimate goal of our project would be to adapt and develop the culture of dinoflagellates in external photobioreactors. It is obvious that complex molecules create new problems to be solved. On our side, we are developing a simple NMR methodology to establish the configuration of stereogenic centers in five-membered rings, which are common in this kind of compounds. This approach includes the synthesis of models that will be used to confirm theoretical approaches and we also try to establish their biosynthetic origins. In addition, the interest of this group of substances is mainly based on their potent biological activities that include new modes of action. Regarding the inhibitory activity of protein phosphatases, the design of this kind of selective inhibitors is the main challenge in this field nowadays. Therefore, we have undertaken structural and conformational studies in solution of AO and analogues and theoretical docking calculations to determine a plausible binding mode. These studies will continue aiming to find simplified molecules fulfilling the necessary structural requirements to achieve a selective inhibition of PP1 and PP2A. Data from in vitro inhibitory activity obtained at IUBO will be compared and complemented with the evaluation of biochemical and toxicological effects in neuronal and glial cells cultures developed in UO, which will help us to establish structure-activity correlations and to identify those structural motifs that determine more effective inhibitors in living cells. However, given the structural complexity of protein phosphatases and the cellular regulatory mechanisms they control it may differ significantly from the inhibitory activity determined in the test tube. Furthermore, these studies will be extended to other types of polyethers found in red algae of the genus Laurencia. The group of UAL will study the interaction between animal immune cells and the isolated compounds, evaluating both their toxicity and biological function, for instance

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studying the ability to recognize immunogens of T cells. UO group will analyse the effects on the CNS using in vitro systems of primary cerebellar neurons, glial cells and organotypic cultures. We will study the biochemical pathways involved in the physiological and toxicological effects and on the development of novel neuroprotective therapies. Finally in this project we plan to start small-scale cultures of 50 species of dinoflagellates from IEO collection to assess their bioactivity and select the new organisms for future studies. Número de investigadores/as: 7 Cód. según financiadora: SAF2011-23338-C03-01 Fecha de inicio: 01/01/2012 , 3 años Fecha fin: 31/12/2015 Entidades participantes: Universidad de Oviedo, Universidad de Almería, IUBO-AG Universidad de La Laguna Cuantía subproyecto: 189.970,00 € IP: Dr. D. José Javier Fernández Castro

Compuestos bioactivos de origen marino: aprovechamiento de metabolitos secundarios de dinoflagelados (BIOTECMAR) De entre todos los organismos marinos, las microalgas juegan un papel crucial en los ecosistemas debido a su actividad fotosintética que los convierte en productores primarios. Dentro de dichas microalgas, nuestro proyecto se interesa por el grupo de los dinoflagelados, pues no hay duda de que si se encuentran las condiciones adecuadas podrían llegar a ser auténticas “factorías celulares” de sustancias bioactivas con diferentes aplicaciones. Sobre la base de resultados previos, en este proyecto proponemos desarrollar las condiciones necesarias para llevar a cabo cultivos a gran escala de dinoflagelados con extraordinario interés como Prorocentrum, Amphidinium y Karlodinium. En efecto, hemos encontrado en Prorocentrum nuevos compuestos “SuperCarbonChain” y lactonas macrocíclicas con interesantes bioactividades, además de nuevas toxinas DSP, todo con el fin de incorporarlos a los protocolos de análisis y control en la UE. Paralelamente, pretendemos desarrollar a escala semi-industrial cultivos de Amphidinium, productores de metabolitos con una gran actividad antitumoral,. En la UAL ya se han desarrollado protocolos para el cultivo de Karlodinium que serán utilizados como punto de partida para establecer el cultivo masivo y continuo de Amphidinium, así como para desarrollar procesos de extracción y reciclado del residuo celular en combinación con el IUBO. Con esto, proponemos dar un valor añadido a la biomasa generada con un procesado posterior que permita su aprovechamiento total.

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A pesar del interés de las toxinas y compuestos bioactivos que producen los dinoflagelados, son muy pocos los comercialmente disponibles, siempre a partir de laboratorios especializados y a precios muy elevados. El objetivo final del proyecto sería disponer de fotobiorreactores de decenas de litros con cultivos de los dinoflagelados seleccionados en el proyecto así como de protocolos de procesado y extracción de las biomoléculas de interés. Resulta obvio que moléculas de esta complejidad generan nuevos problemas que han de resolverse que intentaremos resolver desarrollando una metodología por RMN directa y simple con la que poder establecer la configuración de los centros estereogénicos en sistemas flexibles. Otro foco de interés radica en las potentes actividades biológicas de estas sustancias, con modos de acción generalmente desconocidos. Por ello, realizaremos estudios estructurales (experimentales y computacionales) para establecer correlaciones estructura-actividad. Los datos de actividad inhibidora in vitro serán contrastados y complementados con la evaluación de los efectos bioquímicos y toxicológicos en neurosensores desarrollados en la UNIOVI. Estos estudios se extenderán a alcaloides de tipo zoanthamina con actividad antiosteoporótica. Finalmente, tanto en el IUBO como en la UAL se realizará la búsqueda de nuevas sustancias de naturaleza antifouling. Los retos que plantea el proyecto obligan a combinar la generación de nuevo conocimiento, con su aplicación a tecnologías, productos y servicios que en un futuro podrán contribuir al liderazgo científico, tecnológico y empresarial del país. Por tanto, es oportuno llevarlo a cabo dentro de la estrategia Española de Ciencia y Tecnología (ECYT). El proyecto aquí presentado tiene también vocación de crear liderazgo en tecnologías industriales derivadas de la biotecnología, señalada como prioridad clave en el Programa Horizonte 2020 Biomolecules from marine sources: harnessing bioactive metabolites from dinoflagellates Among marine organisms, microalgae play a crucial role in ecosystems as primary producers due to their photosynthetic activity. Our project is interested in dinoflagellates, since there is no doubt that they could become genuine "cell factories" of bioactive substances with different applications. Based on previous results, we propose to develop the suitable conditions to obtain large-scale cultures of dinoflagellates of special interest as Prorocentrum, Amphidinium and Karlodinium. Indeed, we have isolated from Prorocentrum new "SuperCarbonChain" compounds and macrocyclic lactones with interesting bioactivities as well as new DSP toxins, with the aim to incorporate all of them into the EU protocols of toxin analysis. In parallel we intend to develop the production of Amphidinium cultures on a semi-industrial scale, a known producer of metabolites with potent antitumor activity. Since the UAL group has successfully developed protocols for growing strains of Karlodinium, the results from these cultures will be used as starting point to establish continuous mass cultivation of Amphidinium and to develop harvesting processes for recycling the cell debris with the IUBO. This will provide additional benefits associated with biomass generated by post-processing. Despite the interest of toxins and bioactive compounds produced by dinoflagellates, only a few toxins are commercially available usually provided by specialized laboratories with fairly high prices. The ultimate goal would be to adapt and develop the cultures of the previously selected dinoflagellates in photobioreactors of tens of litres, and assess processing protocols for biomolecules extraction of interest. It is obvious that complex molecules create new problems to be solved. For that reason we will try to develop effective methodologies mainly relying on NMR spectroscopy for stereochemical analysis of even complex and flexible systems. In addition, the interest of this group of substances is mainly based on their potent biological activities that include new modes of action. Therefore, structural studies (experimental and computational) will be performed to establish structure-activity correlations. Data from in vitro

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inhibitory activity will be contrasted and complemented with the assessment of the biochemical and toxicological effects in neurosensors developed at UNIOVI. These studies will be extended to zoanthamine type alkaloids with anti-osteoporotic activity. Finally, IUBO and UAL will screen for biologically active compounds that display antifouling activity. Número de investigadores/as: 7 Cód. según financiadora: CTQ2014-55888-C03-01-R Fecha de inicio: 01/01/2014 , 3 años Fecha fin: 31/12/2016 Entidades participantes: Universidad de Almería, IUBO-AG Universidad de La Laguna Cuantía subproyecto: 162.000,00 € IP: Dr. D. José Javier Fernández Castro

Diseño y síntesis de nuevas moléculas moduladoras de dianas terapéuticas a través de estructuras privilegiadas y síntesis orientada a la diversidad Resumen Este proyecto tiene como objetivo la búsqueda y desarrollo de nuevas entidades moleculares con actividad antiinflamatoria, cardioprotectora, antitumoral, antimicrobiana o antiparasitaria. El acceso a las moléculas bioactivas se realizará mediante estrategias eficaces en la ocupación de regiones biológicamente relevante del espacio químico: uso de “Estructuras Privilegiadas” de origen natural, uso de Reacciones Dominó generadoras de complejidad estructural y diversidad de esqueleto bajo una aproximación de Síntesis Orientada a la Diversidad, Síntesis Total Derivada, Quimiomodulación de bioactividades de cabezas de serie, y estudios de modelización molecular. La inflamación es un factor implicado en la patogénesis de diversas enfermedades cardiovasculares [aterosclerosis, daño por isquemia/reperfusión (I/R), miocarditis viral, etc.]. Resultados previos del grupo con diversos tipos estructurales de diterpenos indican su capacidad de actuar en distintas dianas del proceso inflamatorio, siendo NF-kB una vía de señalización común en la acción de estos compuestos. Además, hemos observado la actividad protectora “per se” en ausencia de inflamación que ejercen algunos de estos compuestos, describiendo su potencial como agentes cardioprotectores actuando sobre dianas moleculares implicadas en el control de la viabilidad celular (PI3K, Akt, AMPk, Bax…). En este proyecto se evaluará la capacidad de nuevas estructuras diterpénicas para proteger frente al daño

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cardiaco, en concreto, series químicas obtenidas a partir de diterpenos seleccionados por su actividad antiinflamatoria y/o cardioprotectora (derivados de hispanolona, ácido labdanólico y solidagenona). La actividad antiinflamatoria y/o cardioprotectora de estas moléculas será evaluada en ensayos de screening en cultivos primarios de macrófagos y cardiomiocitos, para el estudio de las dianas moleculares de actuación (vías de señalización a través de TLRs, vías de supervivencia, AMPk, apoptosis…). Estos ensayos nos permitirán seleccionar moléculas activas con actividad cardioprotectora, actividad que será finalmente validada en modelos de I/R tanto celulares como ex vivo: corazón perfundido de Lagendorff. Estas evaluaciones nos llevarán a identificar estructuras candidatas a ser evaluadas in vivo en modelos de patologías cardíacas y permitirán identificar grupos funcionales relevantes en la actividad cardioprotectora. En el campo de los antitumorales principalmente nos centraremos en la familia de proteinas “Signal Transducer and Activator of Transcription” (STAT) y los Receptores de Estrógenos (RE) que son factores de transcripción que regulan el crecimiento, la diferenciaciación, el metabolismo o la supervivencia de numerosos tipos celulares. Estas proteínas son importantes dianas farmacológicas, validadas por numerosos grupos académicos y empresas, en el tratamiento de determinados tipos de cáncer o enfermedades inmunológicas y metabólicas. En la actualidad, existe una elevada demanda por inhibidores potentes y selectivos de la ruta oncogénica Jak2-STAT así como por moduladores selectivos de los RE (SERMs) con mejor perfil clínico. Se evaluará nuevas moléculas procedentes de quimiotecas específicamente diseñada para descubrir nuevos inhibidores JAK2-STAT o SERM. En concreto se evaluarán triarilmetanos altamente funcionalizados y estructuras C6-C3-C6 como SERMs, así como diversos derivados quinónicos heterocíclicos como inhibidores de la ruta oncogénica JAK2-STAT. Se evaluará la eficacia y toxicidad de estas nuevas moléculas. En primer lugar, se utilizará sistemas de búsqueda a mediana escala basados en líneas celulares con sistemas reporteros de luciferasa. Esto permitirá identificar con rapidez a moduladores químicos que actúen a cualquier nivel de la cascada de señalización dependiente de STAT o de RE. Los ensayos E-SCREEN permitirán seleccionar los productos con actividades SERM. En segundo lugar, se evaluará la citotoxicidad en líneas dependientes de JAK2-STAT (HEL) o de RE (T47D) y en linfocitos primarios. En tercer lugar, se evaluará la eficacia de las moléculas más activas en relación con respuestas biológicas concretas (proliferación, apoptosis, migración, invasión celular, formación de colonias, producción de fosfatasa alcalina, calcificación). Finalmente, con las moléculas más activas se realizarán estudios mecanísticos detallados como son: a) fosforilación y translocación nuclear usando técnicas de immunoblotting, GEMSA y microscopia, b) actividad quinasa de Jak2 in vitro y especificidad sobre otras quinasas, c) apoptosis y ciclo celular, d) binding al RE, e) Fármaco-Toxicogenómica predictiva in vitro, y e) las evaluaciones biológicas orientadas, apoyadas en la mejora del diseño químico, permitirán seleccionar la molécula óptima para evaluar su eficacia y toxicidad in vivo. Dado que nuestro grupo muy recientemente ha patentado una serie de productos de origen natural con una potente actividad antimicrobiana en estirpes bacterianas del género Staphylococcus resistentes a meticilina (MRSA) y a vancomicina (HVRSA) que actualmente constituyen un grave problema en los centros hospitalarios, en la presente solicitud accederá a una serie de análogos mediante una aproximación de Síntesis Total Derivada. Por último también abordará la preparación de nuevos derivados de fenalenonas como agentes antiparasitarios. En base a los resultados de actividad biológica, provenientes del cribado frente a las distintas dianas terapéuticas, mejoraremos las propiedades biológicas y/o farmacológicas de las moléculas bioactivas por medio de estudios de relación estructura-actividad (SAR) así como estudios in silico que facilitará el diseño racional de nuevas entidades.

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Synthesis and design of new molecule modulators of therapeutic targets trough priviliged structures and Diversity Oriented Synthesis Abstract The main objective of the present research proposal is the discovery and development of new molecular entities displaying anti-inflammatory, cardioprotective, antitumour, antibacterial or antiparasitic activities. The access to bioactive molecules will carry out through efficient strategies to chart biologically relevant regions in the chemical space. We will use natural “Privileged Structures”, domino reactions to generate diverse molecular skeletons and molecular complexity following a ”Diversity Oriented Synthesis” approach, Diverted Total Synthesis, Chemomodulation of Bioactivies of lead compounds, and Molecular Modeling studies. Inflammation is an important contributor to the pathogenesis of cardiovascular diseases [atherosclerosis, ischemia/reperfusion (I/R) injury, viral myocarditis, etc]. Our previous findings with diterpenes indicate their capacity to interact with different targets of the inflammatory process, being NF- B a common signaling pathway in the action of these compounds. Moreover, we have also observed the “per se” protective activity, in the absence of inflammation exerted by these compounds, and we described their potential as cardioprotective agents, acting at molecular targets involved in the control of cell viability (Akt, PI3K, AMPk, Bax…). This project will evaluate the capacity of new diterpene derivatives for protection against cardiac injury. Chemical series of diterpenes will be prepared from selected diterpenes (hispanolone, labdanolic acid and solidagenone) with proven anti-inflammatory and cardioprotective activities. The anti-inflammatory and/or cardioprotective activities of these molecules will be evaluated by using cell-based screening systems (primary cultures of macrophages and cardiomyocytes), in order to determine molecular targets involved (signaling pathways through TLRs, survival pathways, AMPk, apoptosis…). These screening assays will allow us to choose active molecules with cardioprotective activity, which will be validated in both cellular and ex vivo I/R models, as Lagendorff-perfused heart. This pharmacological approach will led us to identify candidates to be evaluated in animal models of cardiovascular diseases and the relevant functional groups for cardioprotection. Concerning the antitumoral area we will analyze the activities of the "Signal Transducer and Activator of Transcription" (STAT) and the Estrogen Receptor (ER) which are transcription factors that regulate growth, differentiation, metabolism or the survival of many cell types. These proteins are important drug targets, validated by numerous companies and academic groups, for the treatment of certain types of cancer or immune and metabolic diseases. At present, there is a high demand for potent and selective inhibitors of Jak2-STAT oncogenic route as well as ER selective modulators (SERMs) with better clinical profile. Highly functionalized triarymethanes and structures type C6-C3-C6 will be evaluated as SERMs as well as a variety of designed quinonic heterocycles as JAK2-STAT inhibitors. The efficacy and toxicity of these new molecules will be evaluated by using medium scale searching methodology based on luciferase reporter cell lines. This will quickly identify chemical modulators that act at any level of the cascade of STAT- or ER-dependent signaling. E-SCREEN assays allow select products with SERM activity. Secondly, we will evaluate drug cytotoxicity on JAK2-STAT (HEL) or RE (T47D) dependent cells lines as well as primary lymphocytes. Third, we will evaluate the effectiveness of the active molecules in relation to specific biological responses (proliferation, apoptosis, migration, cell invasion, colony formation, alkaline phosphatase production, bone calcification). Finally, with will perform mechanistic studies by using the more active molecules: a) phosphorylation and nuclear translocation using immunoblotting, GEMSA and microscopy, b) in vitro kinase activity of Jak2 and specificity over other kinases, c) apoptosis and cell cycle, d) interaction with ER, e) pharmacogenomic and drug-predictive Toxicogenomic,

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and e) our molecular target-based screening, supported by improved chemical design, will allow us select the optimal molecule to assess its efficacy and toxicity in vivo. Recently, our grroup has patented diverse compounds from natural sources which have strong in vitro antibacterial activities against Gram-positive bacteria; including multiresistant Staphylococcus aureus clinical isolates. In the present Project, several analogues of these compounds will be synthesized following a Diverted Total Synthesis approach. We will also carry out the preparation of new fenalenones derivatives as antiparasitic agents. From the obtained results in the assays against the several therapeutic targets, we will improve the biological and pharmacological properties of the bioactive molecules through SAR (Structure-Activity relationships) and in silico studies. These types of studies will allow us the rational design of new molecules. Número de investigadores/as: 9 Cód. según financiadora: SAF2012-13296-C03-01 Fecha de inicio: 01/01/2013, 3 años Fecha fin: : 30/09/2015 Entidades participantes: IUBO-AG Universidad de la Laguna, Universidad de Las Palmas de Gran Canaria, Universidad Complutense de Madrid Cuantía subproyecto: 210.000.00 € IP: Dra. Dña. Ana Estevez Braun

Sistemas de extracción miniaturizados basados en nuevos nanomateriales: aplicación a los campos agroalimentario, medioambiental y bioanalítico Resumen A pesar de que en los últimos años se ha producido una auténtica revolución en la búsqueda de nuevos nanomateriales, su aplicación en el campo de la Química Analítica, sobre todo en el campo de las técnicas de separación, no ha sido totalmente explorada. De hecho, el número de aplicaciones desarrolladas hasta la fecha no es demasiado alto, a lo que hay que añadir que generalmente se ha aplicado a un número limitado de compuestos así como a matrices relativamente sencillas. Es por ello que se hace necesario explorar al máximo las posibilidades de estos nuevos nanomateriales así como estudiar su viabilidad, sobre todo para el desarrollo de nuevos procedimientos de preparación de muestra, ya que continúan jugando un papel fundamental a pesar de los grandes desarrollos que se han producido a nivel instrumental. Uno de los objetivos fundamentales de este proyecto es el diseño, la síntesis y caracterización de nuevos nanomateriales así como su aplicación como nuevos sorbentes de extracción

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altamente selectivos en campos donde su explotación ha sido más que limitada. La finalidad será demostrar su viabilidad para la extracción de migrantes de plásticos (ftalatos) de diferentes matrices altamente complejas. Además, la enorme posibilidad de funcionalización/modificación de los nanomateriales permitirá aumentar su afinidad hacia los compuestos de interés, lo que los hace diseñables (extracción inteligente) para extracciones selectivas en matrices complejas, como las que se pretenden abordar. De entre los nanomateriales que se han utilizado en las técnicas de preparación de muestra, los MOFs (materiales con redes híbridas metaloorgánicas, también denominados molecular organic frameworks), el grafeno y las nanopartículas magnéticas están jugando un papel cada vez más relevante, sobre todo cuando se combinan con polímeros de impronta molecular (MIPs) lo que les confiere una mayor selectividad. Son precisamente estos nuevos materiales los que se pretenden utilizar en tres ámbitos fundamentales donde la Química Analítica juega un papel preponderante: el campo alimentario, medioambiental y bioanalítico. Miniaturized extraction sistems based on new nanomaterials: applications to the agroalimentary, environmental and bioanalitic fields Summary Although in recent years there has been a revolution in the search for new nanomaterials, their application in the field of Analytical Chemistry, especially in the field of separation techniques has not been fully explored. In fact, the number of applications developed to date is not too high. Additionaly, it has been generaly applied to a limited number of compounds as well as relatively simple matrices. That is why it is necessary to explore the full potential of these new nanomaterials and to study their viability, especially for the development of new procedures for sample preparation, as they continue to play a key role despite the major developments that have appeared at instrumental level. One of the primary objectives of this project is the design, synthesis and characterization of new nanomaterials and their application as highly selective extraction sorbents in areas where their use has been more limited. The purpose will be to demonstrate their feasibility for the extraction of plastic migrants (phthalates) from different highly complex matrices. Besides, the huge possibility of their functionalization/modification will increase their affinity for the compounds of interest. This makes them designable (intelligent extraction) for the selective extraction of complex matrices, such as those intended to address. Among the nanomaterials that have been used in sample preparation techniques, MOFs (molecular organic frameworks), graphene and magnetic nanoparticles are playing an increasingly important role, especially when combined with molecularly imprinted polymers (MIPs ) which gives them greater selectivity. It is precisely these new materials the ones that will be used in three key areas where Analytical Chemistry plays a major role: the food, environmental and bioanalytical fields. Número de investigadores/as: 7 Cód. según financiadora: CTQ2014-57195-P Fecha de inicio: 01/01/2015, 3 años Fecha fin: 31/12/2017 Entidades participantes: Universidad de La Laguna Cuantía subproyecto: 76.230,00 € IP1: Dr. D. Miguel Angel Rodríguez Delgado IP2: Dr. D. Javier Hernández Borges

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Receptores moleculares como modelos para el estudio de las interacciones no covalentes y sus consecuencias Resumen El proyecto propuesto pretende realizar un estudio de las interacciones no covalentes que gobiernan el reconocimiento molecular y el plegamiento de las moléculas orgánicas, y sus consecuencias. Con el fin de comprender a fondo el papel que juegan dichas interacciones, nuestro grupo de investigación ha recurrido al diseño y desarrollo de modelos moleculares sencillos que permitan emular algunos de los procesos que ocurren en los distintos fenómenos biológicos, tales como: el reconocimiento quiral, el refuerzo del reconocimiento molecular y quiral, la cooperatividad entre las distintas interacciones, el plegamiento molecular, el auto-ensamblaje y la catálisis asimétrica. Para conseguir estos objetivos hemos elegido como modelos de estudio: receptores moleculares y péptidos no naturales. Dentro de los receptores moleculares dirigimos nuestros esfuerzos a tres tipos: 1) receptores quirales de cationes, 2) nuevos receptores cóncavos basados en núcleos de benzociclotrímeros, y 3) nuevas plataformas moleculares basadas en la unidad de tripticeno. Con los receptores quirales de cationes pretendemos estudiar el efecto isotópico y de los aniones en la discriminación quiral de sales de amonio de aminoácidos, y la cooperatividad entre el equilibrio conformacional de los receptores libres y sus afinidades por los sustratos. Teniendo en cuenta los conocimientos adquiridos realizaremos el diseño, síntesis y estudio de nuevos receptores quirales de cationes. Por otro lado, desarrollaremos una nueva aproximación sintética a los receptores benzociclotrímeros, los cuales serán utilizados para el reconocimiento de sales de amonio cuaternarias tales como la acetilcolina, y adicionalmente, estas plataformas moleculares serán incorporadas a la creación de nuevas cápsulas moleculares a través del auto-ensamblaje de dos unidades complementarias por medio de enlaces de hidrógeno. Adicionalmente, incorporaremos el tripticeno en el diseño y preparación de unidades de glicolurea extendidas capaces de auto-ensamblarse en nanotubos moleculares, o de transformarse en cucurbiturilos extendidos que generarán nuevas cápsulas moleculares de gran tamaño. Por último, pretendemos desarrollar nuevos catalizadores dipeptídicos basados en unidades de ε-aminoácidos y de prolinas. Considerando los conocimientos de las interacciones no covalentes adquiridos a través de los distintos modelos, incorporaremos elementos de control conformacional y analizaremos su influencia en algunas reacciones asimétricas.

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Molecular receptors as models for the study of non-covalent interactions and their consequences. Summary The present propose will aim the study of non-covalent interactions that govern molecular recognition and folding of the organic molecules, and their consequences. Our research group has designed and developed molecular models to emulate some of the processes that occur in several biological phenomena, such as: chiral recognition, reinforcement of molecular and chiral recognition, cooperativity between different interactions, molecular folding, self-assembly and asymmetric catalysis. In order to gain deeper understanding in the role of these interactions, we have chosen as study models: molecular receptors and unnatural peptides. Concerning the molecular receptors, we are focusing our efforts on three different types: 1) chiral receptors for cations, 2) new receptors based on benzocyclotrimers cores, and 3) new molecular platforms based on triptycene unit. With the chiral receptors for cations, we plan to study the isotopic and the anions effect in the chiral discrimination of ammonium salts of amino acids, and the cooperativity between the conformational equilibrium of the free receptors and their affinity for their substrates. With the knowledge acquired, we will design and synthesize new chiral receptors for cations. Furthermore, we will develop a new synthetic approach to benzocyclotrimer receptors, which will be used for recognition of quaternary ammonium salts such as acetylcholine. Additionally, these molecular platforms will be incorporated into the development of new molecular capsules through self-assembly of two complementary units using hydrogen bonds. Moreover, we will incorporate the triptycene in the design and preparation of extended glycoluril units to self-assemble into molecular nanotubes or in the synthesis of extended cucurbiturils to generate new large molecular capsules. Finally, we intend to develop new dipeptide catalysts based on ε-amino acid and proline units. Considering the knowledge of non-covalent interactions acquired through the different models, we will incorporate elements of conformational control and evaluate their influence in asymmetric reactions. Número de investigadores/as: 3 Cód. según financiadora: CTQ2014-59649-P Fecha de inicio: 01/01/2015, 4 años Fecha fin: 31/12/2018 Entidades participantes: Consejo Superior de Investigaciones Científicas Cuantía proyecto: 79860 € IP: Dr. Tomás Martín Ruiz

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La regulación de la liberación cuántica de neurotransmisores en la célula cromafín por factores vesiculares�

Resumen Las células cromafines de la médula adrenal son el modelo más utilizado para estudiar los mecanismos que subyacen en la neurosecreción. Estas células almacenan en sus vesículas secretoras altísimas concentraciones de catecolaminas y otros solutos, que serán liberados por exocitosis. Durante los últimos años en nuestro laboratorio hemos ido caracterizando el papel que los principales componentes intravesiculares (las cromograninas, los H+ y el Ca2+) ejercen en el almacenamiento de las catecolaminas y en su exocitosis. Igualmente, varios grupos, incluido el nuestro hemos demostrado que la acumulación vesicular de sustancias exógenas (falsos transmisores) está detrás de buena parte de los efectos terapéuticos de algunos fármacos antihipertensivos, antiepilépticos y antidepresivos. Recientemente, hemos comenzado a estudiar el cuantitativamente segundo mayor componente vesicular, el ATP que sorprendentemente está presente en todas las vesículas secretoras de todos los seres vivos conocidos. Con el desarrollo de este proyecto nos hemos planteado: a) Evaluar el papel del ATP como agente osmótico negativo, facilitador de la agregación de las catecolaminas vesiculares. b) Completar el estudio de las interacciones entre los componentes cuantitativamente importantes del cóctel intravesicular: catecolaminas, ATP, calcio, cromograninas y pH. c) Caracterizar y medir la distribución citosólica del ATP en condiciones basales y frente a estímulos secretores. d) Evaluar la posible contribución del ATP en el almacenamiento de catecolaminas, en el movimiento de las vesículas y en su exocitosis y e) Intentar verificar la hipótesis del papel de reservorio funcional de las vesículas que no se liberan ante estímulos secretagogos. Hasta la fecha todos los estudios en células cromafines se han desarrollado con poblaciones mixtas adrenérgicas y noradrenérgicas. Tenemos ahora una cepa de ratones PNMT-KO que carecen de adrenalina, ello nos permite comparar las interacciones entre la noradrenalina y los demás componentes intravesiculares. Utilizaremos diversas aproximaciones en células cromafines, PC12, células artificiales y experimentos in vitro. Emplearemos técnicas experimentales de biología celular y molecular (expresión heteróloga, silenciamiento, inmunofluorescencia, westernblot, citometría de flujo), electroquímicas (amperometría, FIA), de microscopía (TIRFM, confocal, electrónica, fuerzas atómicas y de efecto túnel) y analíticas (HPLC, osmometría, calorimetría ITC, dispersión lumínica dinámica DLS). Pretendemos completar así nuestra visión de cómo se alcanza la altísima concentración de neurotransmisores en las vesículas secretoras. En comparación con los mecanismos

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involucrados en el transporte y en la fusión vesicular los mecanismos de concentración y complejación intravesicular se han estudiado muy poco. Aun con los escasos datos experimentales disponibles, su malfunción parece estar detrás de un buen número de enfermedades como la hipertensión arterial, ciertos tipos de epilepsia y algunas enfermedades neurodegenerativas. Número de investigadores/as: 9 Cód. según financiadora: MINECO Fecha de inicio: 01/07/14, Fecha fin: 31/12/2017 Entidades participantes: IUBO- AG Universidad de La Laguna, Cuantía subproyecto: 215.000 €. IP: Dr. Ricardo Borges Jurado

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Improving Biomedical Research and Innovation in the Canary Islands To unlock and develop the research and innovation potential of the Centre for Biomedical Research of the Canary Islands (CIBICAN), a coherent series of activities have been designed through the development of this project (IMBRAIN). From a recent SWOT analysis, several impediments have been identified that must be overcome to maximize our research capacities. They include the isolation from decision−making centers and resources, the excessive cost and effort required to coordinate and collaborate in projects and to disseminate research achievements both into the science community and the society. In addition, despite the quality of the research teams and their focus on priority areas, the problems of recruiting experienced new researchers, technical staff and innovation managers remain a serious handicap that we are strongly committed to overcome. The main strategic objective of this project is to increase the quality of research at CIBICAN, and to build its innovation capacity to become a leading centre in Biomedicine and the Health Sciences. It will have a significant impact in promoting regional economic and social development, and in spreading of health knowledge into the outermost EU regions and the near African countries. This will be achieved through the following measures: 1) Exchange of know-how and experience with EU research partnering organizations; 2) Recruitment of experienced researchers, technical staff and innovation manager; 3) Upgrading of research equipment, based on existing infrastructure and core facilities; 4) Elaboration of a strategic IP development plan for IP management and protection and innovation capability building; 5) Dissemination of knowledge on health and increase the visibility of CIBICAN activities at regional, national and European levels. In addition, an ex−post evaluation facility will be developed at the end of the project to define specific strategy actions for long−term sustainable development. http://www.ull.es/view/institucional/ull/Cibican-Imbrain/es

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Insights into the Neanderthals and their demise from the study of microscopic and molecular charred matter in Middle Palaeolithic sediments (ERC-CoG-2014-PALEOCHAR)

Abstract Who were the Neanderthals and what caused their demise? To answer these questions, the classic approach in archaeology relies on the analysis of the Neanderthals' stone-tool assemblages and the mineralized bone remains of their dietary intake. Although this approach has yielded a great deal of important information about the Neanderthals’ fate, it is also limited in the sense that the only evidence that is considered is in-organic in nature. In this ERC Consolidator Grant project we attempt to approach these questions by considering microscopic and molecular evidence that is organic in nature. By studying the organic sedimentary record at such fine scales, we are able to extract information about, for example, the fat contents of the Neanderthal food, the way they made fire, the arrangements of their living spaces, their surrounding vegetation and the climatic conditions where they lived. By combining these different sources of information we aim to provide a more complete picture of the Neanderthal world. Specifically, the PALEOCHAR project examines how Neanderthal diet, fire technology, settlement patterns, and surrounding vegetation at a local scale (individual sites) were affected by changing climatic conditions. To do so, the project will integrate methodologies from micromorphology and organic geochemistry. A key and innovative aspect of the project is the consideration of microscopic and molecular evidence that is both organic and charred in nature. Our recent experimental and geoarchaeological work on Palaeolithic fire has led to the discovery of black layers from archaeological fireplaces as invaluable contexts of preserved organic matter. The black layers typically documented in Middle Palaeolithic hearths represent the charred ground beneath the fire. Therefore, they can be considered as snapshots of living floors, rich in residues from human activity as well as from soils and vegetation of the natural surroundings. Crucially, experimental data has shown that the average temperatures associated with black layers – below 300°C on average - are high enough for the charring of organic compounds and to make them unappealing to biodegrading soil fauna, but not as high

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as to destroy their biomarker chemical fingerprints. Therefore, once charred, organic compounds may preserve well within sediment for indefinite periods of time as long as the sedimentary environment does not undergo strong diagenesis. The PALEOCHAR project will target this important window of organic matter preservation by exploring the black layers of intact Neanderthal fireplaces. Número de investigadores/as: 8 Cód. según financiadora: ERC-CoG-2014-PALEOCHAR Fecha de inicio: 01/09/2015 , 5 años Fecha fin: 31/08/2020 Entidades participantes: European Research Council; Massachusetts Institute of Technology; IUBO- AG Universidad de La Laguna Cuantía subproyecto: 1.996.750,40 € IP: Dr. Carolina Mallol Duque

Neandertal Fire Technology Abstract The Neandertal Fire Technology Project aims to advance our knowledge on different aspects of Neandertal behavior in regards to fire through an interdisciplinary approach to the formation of archaeological combustion features. Archaeological combustion features represent complex sequences of events, many of which might not be related to the making of the fire. These include anthropogenic activities carried out around the fire, post-combustion activities such as sweeping or trampling, and a wide array of geogenic and biogenic post-depositional processes that may alter the original structure and composition of hearths. In our opinion, in order to interpret an archaeological combustion feature from a behavioral perspective it is necessary to determine its formation processes first. This project has been previously funded by the Leakey Foundation, in 2010, when we started to generate a corpus of interdisciplinary data on experimental, archaeological (Middle Palaeolithic) and ethnoarchaeological combustion structures, and in 2013, when we extended our experiments to incorporate rocky substrates for fire and we excavated Neandertal fires dating to around 90 Ka at Abric del Pastor, Alcoy, Spain. Our 2015 project is focused on an

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investigation of the effects of weathering and bioturbation on open air fires, using some of the experimental fires left in situ since 2010. In addition, we are continuing to excavate at Abrid del Pastor and have opened a new research line on archaeomagnetism to try to discern between two or more fire places that are found on a single surface but could belong to different time periods. Número de investigadores/as: 10 Cód. según financiadora: NFT-2015 Fecha de inicio: 01/07/15, 1 año Fecha fin: 31/12/2016 Entidades participantes: IUBO- AG Universidad de La Laguna, Universidad de Burgos, Max Plank Institute. Cuantía subproyecto: 20.659,37 €. IP: Dr. Carolina Mallol Duque

Una alternativa quimioterápica en el tratamiento del cancer: Quimiomodulación de un inductor de apoptosis, withaferina A, cabeza de serie aislada de un endemismo canario. Resumen Un paso clave en el diseño y desarrollo de fármacos es la optimización de las propiedades farmacológicas (quimiomodulación) de un cabeza de serie, mediante la preparación de una colección de análogos (quimioteca) y su posterior evaluación. Además, en la última década la industria farmacéutica ha re-dirigido sus esfuerzos sustituyendo el paradigma de una patología - una diana por el desarrollo de fármacos con múltiples dianas (compuestos promiscuos) que han demostrado ser efectivos, especialmente en enfermedades complejas como el cáncer o SIDA. En este contexto, los productos naturales (PNs) representan un extraordinario punto de partida para la identificación de nuevas entidades químicas con potencial terapéutico, dada su amplia diversidad estructural y capacidad de interaccionar con múltiples receptores (estructuras privilegiadas). Ejemplo de ello, es la Withaferina A, PN con un perfil polifamacológico que además, según nuestras investigaciones previas, se presenta como metabolito mayoritario en Withania aristata, especie endémica de Canarias ampliamente usada en la medicina tradicional. En el Proyecto que planteamos en esta convocatoria pretendemos desarrollar una quimioteca (colección de análogos) a partir del cabeza de serie, Withaferina A, con una potente actividad apoptótica frente a un panel de células cancerosas, lo que permitirá optimizar sus propiedades físico-químicas y farmacológicas así como

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profundizar en el conocimiento del mecanismo acción por el cual ejerce su efecto anticancerígeno. Esta quimioteca se desarrollará siguiendo diversas estrategias, entre las que se incluyen: variación de sustituyentes, preparación de series homólogas, bioisósteros, transformaciones basadas en la unión de elementos activos y formación de compuestos híbridos, estrategia que plantea reemplazar el uso actual de tratamientos combinados (cóctel de fármacos) y reducir la aparición de resistencia a la quimioterapia. Asimismo, se plantea el desarrollo de estudios de modelización molecular tipo 3D-QSAR para profundizar en el conocimiento del mecanismo acción de estos compuestos, ya que a pesar de los numerosos estudios dirigidos a su elucidación éste es aún incierto. Pretendemos con ello avanzar en el desarrollo de anticancerígenos con potencial clínico. Número de investigadores/as: 4 Cód. según financiadora: SALUCAN03 Fecha de inicio: 01/01/2015, 3 años Fecha fin: 31/12/2017 Entidades participantes: IUBO- AG, Universidad de La Laguna Cuantía proyecto: 39.099 IP: Dra. Isabel López Bazzocchi

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Chemical programming of Toll like Receptor 4: Design, synthesis and biological studies of prostatecancer vaccines The IOF proposal, TLRPROSTATE, consists of a 24 month outgoing phase to The Scripps Research Institute in San Diego, California, and a 12 month return phase to the Instituto de Productos Naturales y Agrobiología (IPNA-CSIC) for a total of 36 months. TLRPROSTATE will use advanced methods in synthetic biology to develop synthetic vaccines against prostate cancer, which is the second most common cancer worldwide for men. The project will consist of the design, synthesis and biological evaluation of synthetic vaccines that will chemically stimulate the toll-like receptors and therefore create an immune response. This exciting research area will increase Miranda’s expertise and knowledge in the field of synthetic biology as well as in the synthesis of complex organic molecules. During the return phase, Miranda will integrate his research findings into the studies carried out by the research group at IPNA. The return of knowledge and skills to the Canary Islands, Spain, will take place at a time when there is an increasing support from the government and also European authorities for the development of the Canary Islands as a nerve center in Biomedical studies through research programs partially financed by European funding. Beneficiario: Dr. Pedro O. Miranda Chinea Cód. según financiadora: 623155-TLRPROSTATE Fecha de inicio: 05/01/2015 , 3 años Fecha fin: 05/01/2018 Entidades participantes: Consejo Superior de Investigaciones Científicas; The Scripps Research Institute Cuantía proyecto: 341.387,10 € Científico Responsable: Dr. Juan I. Padrón Peña

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Búsqueda de metabolitos bioactivos en sistemas de arrecifes veracruzanos: estudios estructurales, farmacológicos y biotecnológicos Si bien es cierto que en los últimos cincuenta años se han descubierto un gran número de medicamentos anticancerígenos, antimicrobianos y antifúngicos, se estima que más de la mitad de estas enfermedades aun no tienen un tratamiento satisfactorio, esto es debido al gran número de patologías existentes del cáncer, a los brotes de cepas fármaco-resistentes por el uso inmoderado de medicamentos y a la falta de respuesta del sistema inmune en pacientes inmunodeficientes, por lo que se hace evidente la necesidad de descubrir nuevos fármacos que posean mecanismos de acción más específicos y potentes. Desde el punto de vista de la búsqueda de inhibidores específicos sobre dianas enzimáticas, los procesos de fosforilación y desfosforilación catalizados por enzimas quinasas y fosfatasas están considerados como uno de los mecanismos más importantes en el control de los procesos intracelulares. Las fosfatasas poseen un rol importante en numerosos mecanismos de señalización celular asociados a enfermedades como el cáncer, la diabetes y el alzheimer, lo cual ha motivo a la comunidad científica a diseñar nuevos fármacos contra estas dianas. Por tal motivo, en este proyecto se propone la búsqueda de inhibidores de estas enzimas, particularmente las fosfatasas serina y treonina de tipo 1 (PP1) y 2A (PP2A), ya que son utilizadas como herramientas farmacológicas en el estudio de enfermedades como el cáncer, osteoporosis, diabetes y el alzheimer. Tradicionalmente las principales fuentes de sustancias bioactivas han sido organismos terrestres, su estudio ha permitido el aislamiento de más de la mitad de los principios activos que se comercializan en la actualidad, sin embargo su amplia exploración ha hecho que cada vez sea más difícil encontrar nuevas moléculas con actividades terapéuticas prometedoras. En comparación el mar está lejos de considerarse estudiado, un mundo duro y agresivo y en el que durante millones de años, innumerables formas de vida han evolucionado, originando que estos organismos produzcan una inmensa variedad de compuestos químicos con gran diversidad estructural y potentes actividades farmacológicas. En los últimos 20 años la llamada “Biotecnología Azul”, se ha ido convirtiendo en una de las principales fuentes de sustancias que están siendo usadas para curar de numerosas enfermedades. Este potencial se basa en que los océanos abarcan cerca del 70 % de la extensión del planeta y su diversidad biológica el 95 % de la biosfera. Número de investigadores/as: 6 Cód. según financiadora: CONACyT 220206 Fecha de aprobación: 26/06/2014, 3 añosFecha fin: 26/06/2016

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Entidades participantes: Facultad de Bioanálisis, Facultad de Ciencias Biológicas y Agropecuarias y Centro de Estudio y Servicio en Salud de la Universidad Veracruzana; IUBO-AG de la Universidad de La Laguna. Cuantía proyecto: $ 1400.000 equivale a 77.778 € IP: Dr. D. Francisco A. Cen Pacheco.

Búsqueda de sustancias citotóxicas a partir de hongos microscópicos En este proyecto, se pretende iniciar una nueva línea de trabajo con búsqueda sistemática de sustancias citotóxicas a partir de hongos de diferentes ecosistemas, con la finalidad de aprovechar este potencial químico a partir de estos recursos bióticos prácticamente sin explotar en México. Para ello, se llevará a cabo el aislamiento de cepas fúngicas de tres diferentes tipos de hongos (fitopatógenos terrestres, marinos de algas, esponjas y corales y hongos endófitos de manglar). Después, se realizarán cultivos líquidos y a partir de éstos se harán extractos con cloroformo-metanol y así, seleccionar las cepas que presenten mayor actividad citotóxica en cada uno de los tres grupos. Una vez seleccionadas las tres cepas de interés, se realizarán sus cultivos masivos. Posteriormente, se trabajará con la extracción y purificación por técnicas cromatográficas de los metabolitos bioactivos de los cultivos masivos. Finalmente, los compuestos así obtenidos, serán identificados por técnicas espectroscópicas (RMN, MS, IR, RX, etc) y serán evaluados para determinar nuevamente su citotoxicidad. Entidad finanaciadora: Fondo Sectorial de Investigación para la Educación, Consejo Nacional de Ciencia y Tecnología (CONACYT) Convocatoria Ciencia Básica SEP/CONACYT 2012. (Vigente). CB-2012-01: 181820 Investigador Principal: Angel Trigos Landa,

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Generación de diversidad Esqueletal en lupanos como herramienta en la búsqueda de nuevos agentes anticancerosos Entidad finanaciadora: Fondo Sectorial de Investigación para la Educación, Consejo Nacional de Ciencia y Tecnología (CONACYT) y la Secretaría de Educación Pública (SEP) Méjico) (referencia: 221886) Entidades participantes: Universidad del Yucatan, IPNA-CSIC Duración: 01/01/2015 hasta 31/12/2017. Cuantía: 85.000€ Investigador Principal: Rubén Marrero Carballo, Juan I. Padrón

Caracterizacion quimica de los metabolitos secundarios obtenidos de las especies nativas de la región sur del Perú Según estudios científicos, los metabolitos secundarios obtenidos de recursos marinos son una fuente fundamental de diversidad química estructural por lo que es posible caracterizar y descubrir nuevas estructuras químicas interesantes en las algas Ankistrodesmus sp, Tetraselmis striata (microalgas), y la Lessonia trabeculata y Lessonia nigrescens (macroalgas). Entidad finanaciadora:Ministerio de la Producción. Programa Nacional de Innovación para la Competitividad y Productividad Convocatoria Ciencia Básica CONCYTEC 2014Investigador Principal: Dra. Teresa Cano

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11. PUBLICACIONES

Chemistry - A European Journal 2015, 21, 15053–15445 Prins Cyclization Catalyzed by a FeIII/Trimethylsilyl Halide System: The Oxocarbenium Ion Pathway versus the [2+2] Cycloaddition Sixto J. Pérez, Martín Purino, Pedro O. Miranda, Víctor S. Martín, Israel Fernández, and Juan I. Padrón

Prins & The Revolution: Two mechanistic pathways can be envisaged for the iron(III)-catalyzed Prins cyclization between homoallylic alcohols and non-activated alkenes, namely the classical oxocarbenium pathway and the [2+2] cyclization. The results of this joint experimental–computational study support the classical route.

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Organic Letters 2015, 17, 2912–2915 Synthesis of New Benzocyclotrimer Analogues: New Receptors for Tetramethylammonium Ion Recognition Romen Carrillo, Michael J. Hynes, Víctor S. Martín, Tomás Martín, and Fernando Pinacho Crisóstomo

Using a [2 + 2 + 2] cycloaddition/Mitsunobu reaction sequence, a convenient synthesis to access new benzocyclotrimer analogues has been developed. The new receptors have the geometry and functionality capable of recognizing the tetramethylammonium ion in the gas phase and in solution.

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CrystEngComm 2015, 17, 5081-5093 Synthesis and structural characterization of six Cu(II)-based coordination polymers using the thermally tunable 1,2,3,4-cyclobutanetetracarboxylic acid P. Díaz-Gallifa, O. Fabelo, J. Pasán, L. Cañadillas-Delgado, M. A. Ramírez, A. G. Gallardo, and C. Ruiz-Péreza

The synthesis and structural characterization of new six Cu(II) coordination polymers of formulae {[Cu2(ctc-cbut)(H2O)4]·2(H2O)}n (1), {[Cu5(ctc-cbut)2(OH)2(H2O)8]·7(H2O)}n (2), {[Cu2(ctc-Hcbut)(OH)(H2O)2]·4(H2O)}n (3), [Cu2(ttt-cbut)(H2O)4]n (4), {[Cu2(ttt-cbut)(H2O)4]·4(H2O)}n (5) and {[Cu4(ttt-cbut)2(H2O)2]·3(H2O)}n (6) (ctc-H4cbut = cis,trans,cis-1,2,3,4-cyclobutanetetracarboxylic acid and ttt-H4cbut = trans,trans,trans-1,2,3,4-cyclobutanetetracarboxylic acid), have been carried out, together with a computational study of the electronic and thermal free energies of the four isomers of the given ligand. The compounds 1–3 exhibit the ligand in its commercial cis,trans,cis conformation while 4–6 were synthesized with the trans,trans,trans isomer, after thermal treatment of the ctc-isomer. The topology of the six complexes synthesized have differences in dimensionality: compound 4 shows a one-dimensional topology, compound 3 presents a 2D-topology with a three nodal 4,4,4-c network, while 1, 2, 5 and 6 exhibit a 3D-topology with a binodal network 3,6-c for 1 and [412·612·84] [46]-flu for 2. Compound 5 presents a triply interpenetrated [66]-dia network while 6 exhibits a three-nodal network with [43][44·62][47·610·84] point symbol.

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Amino Acids 2015, 47, 1527-1532 Synthesis and antiproliferative activity of glutamic acid-based dipeptides Gastón Silveira-Dorta, Víctor S. Martín, and José M. Padrón

A small and focused library of 22 dipeptides derived from N,N-dibenzylglutamic acid α- and γ-benzyl esters was prepared in a straightforward manner. The evaluation of the antiproliferative activity in the human solid tumor cell lines HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast), and WiDr (colon) provided γ-glutamyl methionine (GI50 = 6.0–41 μM) and α-glutamyl proline (GI50 = 7.5–18 μM) as lead compounds. In particular, glutamyl serine and glutamyl proline dipeptides were more active in the resistant cancer cell line WiDr than the conventional anticancer drugs cisplatin and etoposide. Glutamyl tryptophan dipeptides did not affect cell growth of HBL-100, while in T-47D cells, proliferation was inhibited. This result might be attributed to the inhibition of the ATB0,+ transporter.

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European Journal of Medicinal Chemistry 2015, 96, 308–317 Synthesis and identification of unprecedented selective inhibitors of CK1ε Gastón Silveira-Dorta, Inês J. Sousa, Miguel X. Fernandes, Victor S. Martín, and José M. Padrón

A small and structure-biased library of enantiopure anti-β-amino alcohols was prepared in a straightforward manner by a simplified version of the Reetz protocol. Antiproliferative activity testing against a panel of five human solid tumor cell lines gave GI50 values in the range 1–20 μM. The reverse screening by computational methods against 58 proteins involved in cancer pointed to kinases as possible therapeutic target candidates. The experimental determination of the interaction with 456 kinases indicated that the compounds behave as selective CK1ε inhibitors. Our results demonstrate that the lead compound represents the first selective CK1ε inhibitor with proven antiproliferative activity in cancer cell lines.

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Chemical Communications 2015, 51, 7027-7030 Oxidation with air by ascorbate-driven quinone redox cycling Gastón Silveira-Dorta, Diego M. Monzón, Fernando P. Crisóstomo, Tomás Martín, Víctor S. Martína, and Romen Carrillo

Transition metal-free oxidation with air at room temperature has been achieved by simply using ascorbate (vitamin C) and catalytic amounts of menadione (vitamin K3). A combination of the mentioned vitamins transforms atmospheric oxygen into hydrogen peroxide, which is able to oxidize arylboronic acids and other chemical moieties.

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Plos One 2015, DOI: 10.1371/journal.pone.0123652 From Broad-Spectrum Biocides to Quorum Sensing Disruptors and Mussel Repellents: Antifouling Profile of Alkyl Triphenylphosphonium Salts Alberto J. Martín-Rodríguez, Jose M. F. Babarro, Fernando Lahoz, Marta Sansón, Víctor S. Martín, Manuel Norte, and José J. Fernández

‘Onium’ compounds, including ammonium and phosphonium salts, have been employed as antiseptics and disinfectants. These cationic biocides have been incorporated into multiple materials, principally to avoid bacterial attachment. In this work, we selected 20 alkyl-triphenylphosphonium salts, differing mainly in the length and functionalization of their alkyl chains, in fulfilment of two main objectives: 1) to provide a comprehensive evaluation of the antifouling profile of these molecules with relevant marine fouling organisms; and 2) to shed new light on their potential applications, beyond their classic use as broad-spectrum biocides. In this regard, we demonstrate for the first time that these compounds are also able to act as non-toxic quorum sensing disruptors in two different bacterial models (Chromobacterium violaceum and Vibrio harveyi) as well as repellents in the mussel Mytilus galloprovincialis. In addition, their inhibitory activity on a fouling-relevant enzymatic model (tyrosinase) is characterized. An analysis of the structure-activity relationships of these compounds for antifouling purposes is provided, which may result useful in the design of targeted antifouling solutions with these molecules. Altogether, the findings reported herein provide a different perspective on the biological activities of phosphonium compounds that is particularly focused on, but, as the reader will realize, is not limited to their use as antifouling agents.

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Journal of Natural Products 2015, 78, pp 712–721 Oxasqualenoids from Laurencia viridis: Combined Spectroscopic–Computational Analysis and Antifouling Potential Francisco Cen-Pacheco, Adrian J. Santiago-Benítez, Celina García, Sergio J. Alvarez-Mendez, Alberto J. Martín-Rodríguez, Manuel Norte, Victor S. Martín, Jose A. Gavín, Jose J. Fernandez, and Antonio Hernandez Daranas

The chemical study of the red alga Laurencia viridis has led to the isolation of four new polyether triterpenoids: 28-hydroxysaiyacenol B (2), saiyacenol C (3), 15,16-epoxythyrsiferol A (4), and 15,16-epoxythyrsiferol B (5). The structures of 2 and 3 were established mainly by NMR data analysis and comparison with the well-known metabolite dehydrothyrsiferol (1). However, due to the existence of a nonprotonated carbon within the epoxide functionality, stereochemical assignments in 4 and 5 required an in-depth structural study that included NOESY data, J-based configuration analysis, comparison with synthetic models, and DFT calculations. The biological activities of the new metabolites and other related oxasqualenoids were evaluated for the first time against a panel of relevant biofouling marine organisms, and structure–activity conclusions were obtained.

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Journal of Natural Products 2015, 78, pp 712–721 Acetate-Derived Metabolites from the Brown Alga Lobophora variegata Adrian Gutierrez Cepeda, José J. Fernańdez, Manuel Norte, Sofia Montalvao, Paıvi Tammela and María L. Souto

Seven new nonadecaketides (1−7), lobophorols A−C, lobophopyranones A and B, and lobophorones A and B, along with the first naturally occurring related metabolites (8−10), were isolated from specimens of Lobophora variegata collected from the Canary Islands. Their structures were determined by extensive spectroscopic methods. In addition, an insight into the biosynthesis of these compounds on the basis of the involvement of type III polyketide synthases is proposed. Lobophorol A (1) showed significant antibacterial activity against Staphylococcus aureus.

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International Journal of Medicinal Mushrooms 2015, 17, 501–509

Isolation and Characterization of Bioactive Metabolites from Fruiting Bodies and Mycelial Culture of Ganoderma oerstedii (Higher Basidiomycetes) from Mexico

Guillermo Mendoza, Jorge Suárez-Medellín, César Espinoza, Angel Ramos-Ligonio, José J. Fernández, Manuel Norte, Ángel Trigos

Various species of the genus Ganoderma have been used for centuries according to oriental tradition as a source of medicines and nutrients. A chemical study of the fruiting bodies and mycelial culture of G. oerstedii was carried out with the idea of isolating and characterizing active natural components present to make use of their potential pharmaceutical application in Mexico. The fruiting bodies and mycelial culture of G. oesrtedii were lyophylized and extracted one after the other with hexane, chloroform, and methanol. Following this process, each substance was compounds (ganodermanondiol, ganoderic acid Sz, and ganoderitriol M) were obtained from fruiting bodies. From the mycelial culture three metabolites, two sterols (ergosterol and cerevisterol), and a new terpene compound (ganoderic acetate from the acid) were obtained. These structures were established based on a spectroscopic analysis mainly using nuclear magnetic resonance and a comparison with data already established 0

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Pharmaceutical Biology 2015, (http://dx.doi.org/10.3109/13880209.2015.1081254)

Antiproliferative effect of extract from endophytic fungus Curvularia trifolii isolated from the ‘‘Veracruz Reef System’’ in Mexico

Alan Couttolenc, Cesar Espinoza, Jose J. Fernández, Manuel Norte, Gabriela B. Plata, Jose M. Padron, Alla Shnyreva, and Ángel Trigos

Context: It is well known that marine fungi are an excellent source of biologically active secondary metabolites, and by year 2011, it was reported that over 400 bioactive metabolites were derived from marine fungi. Objective: This study establishes the basis for future research on antiproliferative compounds of marine endophytes inhabited in the Veracruz Reef System. Material and methods: Isolation of the 34 fungal strains was carried out by microbiological method from samples of sponges, corals, and other biological material from the Veracruz Reef System. The fungal biomass and broth were separated and extracted with a mixture of solvents MeOH:CHCl3. Characterization and molecular identification of the fungal strains were performed through microbiological methods and the analysis of the ITS-rDNA regions. Antiproliferative activity was tested at a dose of 250 mg/mL on human solid tumor cell lines HBL-100, HeLa, SW1573, T-47D, and WiDr by the SRB assay after 48 h-exposure to the fungal extracts. Results: The extracts from five isolates showed an antiproliferative effect against one or more of the tested cell lines (percentage growth 5 50%). The mycelial extract from the isolate LAEE 03 manifested the highest activity against the five cell lines (% PG of 17 HBL-100, 19 HeLa, 23 SW1573, -6 T-47D, and 10 WiDr) and the strain was identified as Curvularia trifolii (Kauffman) Boedijn (Pleosporaceae). Discussion and conclusion: The results obtained indicate that the extract from a marine derived C. trifolii has the antiproliferative effect, thus suggesting that this organism is a good candidate for further analysis of its metabolites.

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Phytochemistry 2015, 117, pp 98–106 Flavonoids from Piper delineatum modulate quorum-sensing-regulated phenotypes in Vibrio harveyi Alberto J. Martín-Rodríguez, Juan C. Ticona, Ignacio A. Jiménez, Ninoska Flores, José J. Fernández, Isabel L. Bazzocchi

Quorum sensing (QS), or bacterial cell-to-cell communication, is a key process for bacterial colonization of substrata through biofilm formation, infections, and production of virulence factors. In an ongoing investigation of bioactive secondary metabolites from Piper species, four new flavonoids (1–4), along with five known ones (5–9) were isolated from the leaves of Piper delineatum. Their stereostructures were established by spectroscopic and spectrometric methods, including 1D and 2D NMR experiments, and comparison with data reported in the literature. The compounds were screened for their ability to interfere with QS signaling in the bacterial model Vibrio harveyi. Four compounds from this series (2, 3, 6, and 7) exhibited remarkable activity in the micromolar range, being compounds 3 and 7 particularly attractive since they did not affect bacterial growth. The results suggest that these flavonoids disrupt QS mediated bioluminescence by interaction with elements downstream LuxO in the QS circuit of V. harveyi, and also, they exhibited a strong dose-dependent inhibition of biofilm formation. The present findings shed light on the QS inhibition mechanisms of flavonoids, underlining their potential applications.

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European Journal of Organic Chemistry 2015, 10, 2256-2261 Oximoaspergillimide, a Fungal Derivative from a Marine Isolate of Aspergillus sp. Faviola Cardoso-Martínez, José M. de la Rosa, Ana R. Díaz-Marrero, José Darias, Luis D'Croz, Claudia Cerella, Marc Diederich, and Mercedes Cueto A new alkaloid, oximoaspergillimide (1), and the known neohydroxyaspergillic (2) and neoaspergillic (3) acids, have been isolated from the extract of a cultured marine-derived fungus (strain CF07002) identified as a member of the genus Aspergillus. The structure of 1 was determined by interpretation of NMR spectroscopic data, and confirmed by synthesis. The antimicrobial and cytotoxic activities of compounds 1–3 were evaluated.

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Organic and Biomolecular Chemistry 2015, 13, 7248-7256 Tanzawaic acids isolated from a marine-derived fungus of the genus Penicillium with cytotoxic activities Faviola Cardoso-Martínez, José M. de la Rosa, Ana R. Díaz-Marrero, José Darias, Luis D'Croz, Claudia Cerella, Marc Diederich, and Mercedes Cueto Tanzawaic acids M (1), N (2), O (3) and P (4) and the known tanzawaic acids B (5) and E (6), have been isolated from an extract of a cultured marine-derived fungus (strain CF07370) identified as a member of the genus Penicillium. The structures of 1–4 were determined based on spectroscopic evidence. The antimicrobial and cytotoxic activities of compounds 1–6 were evaluated.

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Islets 2015, 7, e1078053

Protective effects of epoxypukalide on pancreatic beta-cells and glucose metabolism in STZ-induced diabetic mice Jose F López-Acosta, Pablo Villa-Pérez, Cristina M Fernández-Díaz, Daniel de Luis Román, Ana R Díaz-Marrero, Mercedes Cueto, Germán Perdomo, and Irene Cózar-Castellano Diabetes is a consequence of a decrease on functional -cell mass. We have recently demonstrated that epoxypukalide (Epoxy) is a natural compound with beneficial effects on primary cultures of rat islets. In this study, we extend our previous investigations to test the hypothesis that Epoxy protects -cells and improves glucose metabolism in STZ-induced diabetic mice. We used 3-months old male mice that were treated with Epoxy at 200 g/kg body weight. Glucose intolerance was induced by multiple intraperitoneal low-doses of streptozotocin (STZ) on 5 consecutive days. Glucose homeostasis was evaluated measuring plasma insulin levels and glucose tolerance. Histomorphometry was used to quantify the number of pancreatic -cells per islet. -cell proliferation was assessed by BrdU incorporation, and apoptosis by TUNEL staining. Epoxy treatment significantly improved glucose tolerance and plasma insulin levels. These metabolic changes were associated with increased -cell numbers, as a result of a two-fold increase in -cell proliferation and a 50% decrease in -cell death. Our results demonstrate that Epoxy improves whole-body glucose homeostasis by preventing pancreatic -cell death due to STZ-induced toxicity in STZ-treated mice.

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Journal of Natural Products 2015, en prensa

Additional Insights into the Obtusallene Family: Components of Laurencia marilzae

Adrián Gutiérrez-Cepeda, José J. Fernández, Matías López-Rodríguez, Iván Brito; Manuel Norte, Christian D. Muller and María L. Souto

Marilzanin

The obtusallenes are a significant subset of C15-halogenated acetogenins that incorporate twelve-membered cyclic ethers. We have recently reported the isolation from Laurencia marilzae of 12-epoxyobtusallene IV (1) and its related , -unsaturated carboxylate ester (2), both of special biogenetic relevance. Here we describe, the final step of our study, the isolation of three new analogues (3-5), among these, the first bromopropargylic derivative (3) of this class of macrocyclic C15-acetogenins. The structures were elucidated by NMR data and X-ray analysis. 12-Epoxyobtusallene IV (1), its new isomer 4 and known obtusallene IV were evaluated for their apoptosis-inducing activities in a human hepatocarcinoma cell line.

O

O

HCl

BrH

H H

HO

Br 12

1

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15

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Bio-protocol 2015, en prensa A Bioassay Protocol for Quorum Sensing Studies with Vibrio campbellii Alberto J. Martín-Rodríguez and José J. Fernández

Quorum Sensing (QS), or bacterial cell-to-cell communication, is a finely-tuned mechanism that regulates gene expression on a population density-dependent manner through the production, secretion and reception of extracellular signaling molecules termed autoinducers (AIs). Given that QS plays an important role in bacterial biofilm formation and virulence factor production in many pathogenic strains, QS disruptors have become a hot topic in current antimicrobial research. There are several reporter strains exhibiting QS-regulated phenotypes that have been engineered for the identification of QS inhibitors. With three parallel QS circuits, the bioluminescent marine bacterium Vibrio campbellii (formerly harveyi, Lin et al. 2010) constitutes a complex Gram-negative model for which an extensive body of knowledge exists, including an array of mutant biosensors. However, bioluminescence is the result of complex biochemical networks that converge with cell respiration and fatty acid metabolism. It is also an energy-demanding reaction that strongly depends on the overall metabolic state of the bacterium, consuming up to 1/5 of the cell resources (Munn 2011). Thus, disruption of QS-controlled phenotypes might be the result of toxic side-effects or interference with the above-mentioned biochemical pathways rather than QS signaling. Therefore, adequate control experiments should be included. The protocol described herein provides a method and workflow for the identification of putative QS-disrupting compounds. It can also be easily adapted for other QS studies (e.g. detection of AI molecules)

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Journal of Natural Products 2015, 78, 736–745 Restoration of Chemosensitivity in P-Glycoprotein-Dependent Multidrug-Resistant Cells by Dihydro-β-agarofuran Sesquiterpenes from Celastrus vulcanicola Oliver Callies, María P. Sanchez-Canete, Francisco Gamarro, Ignacio A. Jimenez, Santiago Castanys, and Isabel L. Bazzocchi

Multidrug resistance (MDR) caused by the overexpression of ABC drug transporters is a major obstacle in clinical cancer chemotherapy and underlines the urgent need for the development of new, potent, and safe reversal agents. Toward this goal, reported herein are the structure elucidation and biological activity of nine new (1−9) and four known (10−13) dihydro-β-agarofuran sesquiterpenes, isolated from the leaves of Celastrus vulcanicola, as reversers of MDR mediated by human P-glycoprotein expression. The structures of these compounds were elucidated by extensive NMR spectroscopic and mass spectrometric analysis, and their absolute configurations were determined by circular dichroism studies, chemical correlations (1a, 8a, and 8b), and biogenetic means. Four compounds from this series were discovered as potent chemosensitizers for MDR1-G185 NIH-3T3 murine cells (3, 4, 6, and 7), showing higher efficacies than the classical P-glycoprotein inhibitor verapamil, a first-generation chemosensitizer, when reversing resistance to daunomycin and vinblastine at the lowest concentration tested of 1 μM.

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Journal of Natural Products 2015, 78, 1045-1055 Isolation, Structural Modification, and HIV Inhibition of Pentacyclic Lupane-Type Triterpenoids from Cassine xylocarpa and Maytenus cuzcoina Oliver Callies, Luis M. Bedoya, Manuela Beltrán, Alejandro Muñoz, Patricia Obregón Calderón, Alex A. Osorio, Ignacio A. Jiménez, José Alcamí, and Isabel L. Bazzocchi

As a part of our investigation into new anti-HIV agents, we report herein the isolation, structure elucidation, and biological activity of six new (1−6) and 20 known (7−26) pentacyclic lupane-type triterpenoids from the stem of Cassine xylocarpa and root bark of Maytenus cuzcoina. Their stereostructures were elucidated on the basis of spectroscopic and spectrometric methods, including 1D and 2D NMR techniques. To gain a more complete understanding of the structural requirements for anti-HIV activity, derivatives 27−48 were prepared by chemical modification of the main secondary metabolites. Sixteen compounds from this series displayed inhibitory effects of human immunodeficiency virus type 1 replication with IC50 values in the micromolar range, highlighting compounds 12, 38, and 42 (IC50 4.08, 4.18, and 1.70 μM, respectively) as the most promising anti-HIV agents.

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Molecular Diversity 2015, doi:10.1007/s11030-015-9638-7 [Epub ahead of print] Ring-closing metathesis as key step in the synthesis of Luffarin I, 16-epi-Luffarin I and Luffarin A Aitor Urosa, Isidro S. Marcos, David Díez, Gabriela B. Plata, José M. Padrón, and Pilar Basabe

Natural sesterterpenolides, luffarin I and luffarin A, from Luffariella geometrica have been synthesized, and this is the first reported synthesis of luffarin A. The Yamaguchi esterification of the nor-diterpenic fragment, obtained from (-)-sclareol, with the appropriate furane alcohols yielded the necessary diene intermediates for the synthesis of the target molecules. The key strategic step in this synthesis was the ring-closing metathesis (RCM) reaction of the diene intermediates. This strategy allowed for the synthesis of 16-epi-luffarin I and analogues for structure–activity relationship (SAR) studies. The most active compound exhibited antiproliferative activity against a panel of six human solid tumour cell lines with GI50 values in the range 2.8–15 M.

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Organometallics 2015, 34, 5407-5417 Catalytically generated ferrocene-containing guanidines as efficient precursors for new redox-active heterometallic Platinum(II) complexes with anticancer activity Daniel Nieto, Sonia Bruña, Ana Mª González-Vadillo, Josefina Perles, Fernando Carrillo-Hermosilla, Antonio Antiñolo, José M. Padrón, Gabriela B. Plata, and Isabel Cuadrado

The potential of structurally new ferrocene-functionalized guanidines as redox-active precursors for the synthesis of heterometallic platinum(II)–guanidine complexes with anticancer activity was studied. To this end, an atom-economical catalytic approach was followed by using ZnEt2 to catalyze the addition of aminoferrocene and 4-ferrocenylaniline to N,Nʹ-diisopropylcarbodiimide. Furthermore, reaction of a platinum(II) source with the newly obtained guanidines Fc–N═C(NHiPr)2 (3) and Fc(1,4-C6H4)–N═C(NHiPr)2 (4) provided access to the heterometallic complexes [PtCl2{Fc–N═C(NHiPr)2}(DMSO)] (5), [PtCl2{Fc(1,4-C6H4)–N═C(NHiPr)2}(DMSO)] (6), and [PtCl2{Fc(1,4-C6H4)–N═C(NHiPr)2}2] (7). Electrochemical studies evidence the remarkable electronic effect played by the direct attachment of the guanidine group to the ferrocene moiety in 3, making its one-electron oxidation extremely easy. Guanidine-based Fe–Pt complexes 5 and6 are active against all human cancer cell lines tested, with GI50 values in the range 1.4–2.6 μM, and are more cytotoxic than cisplatin in the resistant T-47D and WiDr cell lines.

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Journal of Natural Products 2015, 78, 93-102 Structure and antimicrobial activity of phloroglucinol derivatives from Achyrocline satureoides Carina Casero; Felix Machin; Sebastián Méndez-Alvarez; Mirta Demo; Ángel G. Ravelo; Nury Perez-Hernández; Pedro Joseph-Nathan

The new prenylated phloroglucinol α-pyrones 1–3 and the new dibenzofuran 4, together with the known 23-methyl-6-O-demethylauricepyrone (5), achyrofuran (6), and 5,7-dihydroxy-3,8-dimethoxyflavone (gnaphaliin A), were isolated from the aerial parts of Achyrocline satureioides. Their structures were determined by 1D and 2D NMR spectroscopic studies, while the absolute configuration of the sole stereogenic center of 1 was established by vibrational circular dichroism measurements in comparison to density functional theory calculated data. The same (S) absolute configuration of the α-methylbutyryl chain attached to the phloroglucinol nucleus was assumed for compounds 2–6 based on biogenetic considerations. Derivatives 7–16 were prepared from 1 and 5, and the antimicrobial activities of the isolated metabolites and some of the semisynthetic derivatives against a selected panel of Gram-positive and Gram-negative bacteria, as well as a set of yeast molds, were determined.Multidrug

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Clinical and Translational Oncology 2015, 17, 74-84 A new family of choline kinase inhibitors with antiproliferative and antitumor activity derived from natural products Ana Estévez-Braun; Ángel G. Ravelo; Elisa Pérez-Sacau; Juan Carlos Lacal.

Choline kinase alpha (ChoKα) is a critical enzyme in the synthesis of phosphatidylcholine, a major structural component of eukaryotic cell membranes. ChoKα is overexpressed in a large variety of tumor cells and has been proposed as a target for personalized medicine, both in cancer therapy and rheumatoid arthritis. Among 59 natural and semisynthetic TPQs tested in an ex vivo system, 14 were highly active as inhibitors of the enzyme ChoKα with IC50 <10 μM. Nine of these were potent antiproliferative agents (IC50 <10 μM) against tumor cells. At least one compound was identified as a new antitumoral drug based on its in vivo activity against xenographs of human HT-29 colon adenocarcinoma cells. The identification of a new family of natural and semisynthetic compounds with potent inhibitory activity against ChoKα and both in vitro antiproliferative and in vivo antitumoral activity supports further research on these inhibitors as potential anticancer agents. Their likely role as antiproliferative drugs deserves further studies in models of rheumatoid arthritis.

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Journal of Cluster Science 2015, 26, 83-91 Linkage Isomerism in [Mo3(μ3-S)(μ2-SSe)3(dtp)3]Cl: Preparation and characterization of Two Isomers with Different Coordination Mode of the μ2-SSe Ligand. Hernandez-Molina, Rita; Gushchin, Artem; Vicent, Cristian; Gili, Pedro.

Two geometrical isomers of the composition [Mo3S4Se3(dtp)3]Cl (dtp is O,Oʹ-diethyldithiophosphate) have been prepared and characterized by multinuclear NMR, electrospray ionization mass spectrometry (ESI–MS) and quantum chemical calculations. The first isomer was prepared by reaction of the aqua cluster ([Mo3(μ3-S)(μ2-Se)3(H2O)9]4+) with a large excess of P4S10/EtOH in 2 M HCl. Its structure corresponds to [Mo3(μ3-S)(μ2-Seax-Seq)3(dtp)3]Cl (1). The second isomer, [Mo3(μ3-S)(μ2-Sax-Seeq)3(dtp)3]Cl (2) was prepared by the reaction of [Mo3S7Cl6]2− with SePPh3 followed by treatment with a stoichiometric amount of P4S10/EtOH. The reason for the isomerism is that the μ2-SSe ligand is coordinated asymmetrically, so that one chalcogen atom is almost coplanar with the Mo3 plane (called equatorial) and the other one is strongly out of the plane (axial). Alternative occupancy of these positions by S or Se leads to a rare kind of linkage isomerism. Each isomer has distinctive spectroscopic signature and fragmentation pattern in ESI–MS. Isomer 2 with μ2-SaxSeeqcoordination mode was found to be slightly more stable than isomer 1 with μ2-SeaxSeq coordination.

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Bioorganic & Medicinal Chemistry Letters 2015, 25(19), 4210-4213 Biological evaluation of angular disubstituted naphthoimidazoles as anti-inflammatory agents Irene Cuadrado-Berrocal, Gema Guedes, Ana Estévez-Braun, Sonsoles Hortelano, Beatriz de Las Heras.

A series of naphthoimidazoles derivatives (3a–3f) were tested for potential anti-inflammatory activity on lipopolysaccharide (LPS)-treated macrophages. Naphthoimidazole 3e exhibited significant inhibitory effects on nitric oxide (NO) production (IC50 <10 μM) and decreased the expression of nitric oxide synthase-2 (NOS-2) and cycloxygenase-2 (COX-2) enzymes. It also inhibited the activation of transcription factor NF-κB. Naphthoimidazole 3e might represent a starting point for the synthesis of new anti-inflammatory naphthoimidazoles derivatives.

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Molecules 2015, 20(8), 13854-13863 Antiproliferative and Structure Activity Relationships of Amaryllidaceae Alkaloids. Juan C. Cedrón, Ángel G. Ravelo, Leticia G. León, José M. Padrón, Ana Estévez-Braun.

The antiproliferative activity of a set of seven natural Amaryllidaceae alkaloids and 32 derivatives against four cancer cell lines (A2780, SW1573, T47-D and WiDr) was determined. The best antiproliferative activities were achieved with alkaloids derived from pancracine (2), haemanthamine (6) and haemantidine (7). For each skeleton, some structure-activity relationships were outlined.

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CHEMMEDCHEM 2015, 10, 1403-1412 Synthesis of 4,4'diaminotriphenylmethanes with potential selective estrogen receptor modulator (SERM)-like activity Gema Guedes, Ángel Amesty, Roberto Jiménez-Monzón, Jorge Marrero-Alonso, Mario Díaz, Leandro Fernández-Pérez, and Ana Estévez Braun

In this study, a series of new 4,4ʹ-diaminotriphenylmethanes was efficiently synthesized from aromatic aldehydes and 2,5-dimethoxybenzenamine under microwave irradiation in the presence of Sc(OTf)3 as a catalyst. Antiproliferative activity was assessed by using the MCF-7 estrogen receptor (ER)-positive breast cancer cell line, and antagonist/agonist transcriptional activities were determined. Docking studies and competition studies of triphenylmethanes and radiolabeled estradiol determined that these compounds do not bind the ER, indicating that triphenylmethane-induced changes in proliferative and transcriptional activities differ from conventional mechanisms of action triggered by other selective ER modulators.

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Chemistry A European Journal 2015, 21, 2835-2844. Mechanism of [3+2] Cycloaddition of Alkynes to the [Mo3S4(acac)3(py)3][PF6] Cluster Pino-Chamorro, Jose Angel; Gushchin, Artem L.; Fernandez-Trujillo, M. Jesus; Hernandez-Molina, Rita; Vicent, Cristian; Algarra, Andres G.; Basallote, Manuel

A study, involving kinetic measurements on the stopped-flow and conventional UV/Vis timescales, ESI-MS, NMR spectroscopy and DFT calculations, has been carried out to understand the mechanism of the reaction of [Mo3S4(acac)3(py)3][PF6] ([1]PF6; acac=acetylacetonate, py=pyridine) with two RC CR alkynes (R=CH2OH (btd), COOH (adc)) in CH3CN. Both reactions show polyphasic kinetics, but experimental and computational data indicate that alkyne activation occurs in a single kinetic step through a concerted mechanism similar to that of organic [3+2] cycloaddition reactions, in this case through the interaction with one Mo(μ-S)2 moiety of [1]+. The rate of this step is three orders of magnitude faster for adc than that for btd, and the products initially formed evolve in subsequent steps into compounds that result from substitution of py ligands or from reorganization to give species with different structures. Activation strain analysis of the [3+2] cycloaddition step reveals that the deformation of the two reactants has a small contribution to the difference in the computed activation barriers, which is mainly associated with the change in the extent of their interaction at the transition-state structures. Subsequent frontier molecular orbital analysis shows that the carboxylic acid substituents on adc stabilize its HOMO and LUMO orbitals with respect to those on btd due to better electron-withdrawing properties. As a result, the frontier molecular orbitals of the cluster and alkyne become closer in energy; this allows a stronger interaction.

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The Journal of Organic Chemistry 2015, 80, 6447−6455 Synthesis of Luffarin L and 16-epi-Luffarin L using a temporary silicon-tethered ring-closing metathesis reaction Aitor Urosa, Isidro S. Marcos, David Díez, José M. Padrón, and Pilar Basabe

The first synthesis of luffarin L (1) and 16-epi-luffarin L (2) by a silicon-tethered ring closing metathesis as a key step has been achieved. The stereochemistry and absolute configuration of the natural sesterterpenolide luffarin L (1) and a new route for the stereoselective synthesis of sesterterpenolides with a luffarane skeleton have been established.

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Chemistry a European Journal 2015, 21, 8237-8241 Dienamine and Friedel–Crafts one-pot synthesis, and antitumor evaluation of diheteroarylalkanals María Frías, José M. Padrón, and José Alemán

An asymmetric synthesis of diheteroarylalkanals through one-pot dienamine and Friedel–Crafts reaction is presented. The reaction tolerates a large variety of substituents at different positions of the starting aldehyde and also in the indole nucleophile, and a range of diheterocyclic alkanals can be achieved. Furthermore, we have studied the antiproliferative activity of these new compounds in representative cancer tumor cell lines.

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The Journal of Organic Chemistry 2015, 80, 4566−4572 Biomimetic synthesis of two salmahyrtisanes: Salmahyrtisol A and Hippospongide A María Martín, Aitor Urosa, Isidro S. Marcos, David Díez, José M. Padrón, and Pilar Basabe

Sesterterpenes with a salmahyrtisane skeleton have been synthesized for the first time. (−)-Sclareol has been selected as a precursor for the synthesis of two novel natural products: salmahyrtisol A (1) and hippospongide A (2). Our results represent a biomimetic approach to obtaining salmahyrtisanes from hyrtiosanes. Salmahyrtisol A has shown an activity comparable to that of the standard anticancer drugs in the cell lines A549, HBL-100, HeLa, and SW1573.

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Marine Drugs 2015, 13, 2407-2423 Synthesis and bioactivity of Luffarin I Aitor Urosa, Isidro S. Marcos, David Díez, Anna Lithgow, Gabriela B. Plata, José M. Padrón, and Pilar Basabe

The first synthesis of Luffarin I, sesterterpenolide isolated from sponge Luffariella geometrica, has been accomplished from commercially available sclareol. The key strategy involved in this synthesis is the diastereoselective reduction of an intermediate ketone. Luffarin I against human solid tumor cell lines showed antiproliferative activities (GI50) in the range 12–17 μM.

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European Journal of Medicinal Chemistry 2015, 96, 308-317 Synthesis and identification of unprecedented selective inhibitors of CK1ε Gaston Silveira-Dorta, Inês J. Sousa, Miguel X. Fernandes, Víctor S. Martín, and José M. Padrón

A small and structure-biased library of enantiopure anti-β-amino alcohols was prepared in a straightforward manner by a simplified version of the Reetz protocol. Antiproliferative activity testing against a panel of five human solid tumor cell lines gave GI50 values in the range 1–20 μM. The reverse screening by computational methods against 58 proteins involved in cancer pointed to kinases as possible therapeutic target candidates. The experimental determination of the interaction with 456 kinases indicated that the compounds behave as selective CK1ε inhibitors. Our results demonstrate that the lead compound represents the first selective CK1ε inhibitor with proven antiproliferative activity in cancer cell lines.

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New Journal of Chemistry 2015, 39, 2657-2668 Efficient synthesis of some new antiproliferative N-fused indoles and isoquinolines via 1,3-dipolar cycloaddition reaction in an ionic liquid Tushar R. Sutariya, Balvantsingh M. Labana, Narsidas J. Parmar, Rajni Kant, Vivek K. Gupta, Gabriela B. Plata, and José M. Padrón

Syntheses of some new pyrrolo-fused pyrrolo[1,2-a] indole derivatives have been achieved by combining N-allyl-indole-2-carbaldehyde with a variety of N-alkyl-glycine esters as well as tetrahydroisoquinolines in an ionic liquid, triethylammonium acetate (TEAA), a recyclable reaction medium, via intramolecular [3+2] cycloaddition reaction. This new method is highly efficient, and the ionic liquid employed is recyclable. The stereochemistry of all the compounds was confirmed by 2D NMR NOESY and in some cases single crystal X-ray diffraction data. The in vitroscreening of all new candidates against various bacterial strains and representative human solid tumor cell lines, A549 (lung), HeLa (cervix), SW1573 (lung), T-47D (breast) and WiDr (colon), revealed that many of them have good antibacterial, antifungal and antitubercular and antiproliferative activities.

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European Journal of Medicinal Chemistry 2015, 94, 63-72 Phenolic thio- and selenosemicarbazones as multi-target drugs Verónica Calcatierra, Óscar López, José G. Fernández-Bolaños, Gabriela B. Plata, and José M. Padrón

A series of isosteric phenolic thio- and selenosemicarbazones have been obtained by condensation of naturally-occurring phenolic aldehydes and thio(seleno)semicarbazides. Title compounds were designed as potential multi-target drugs, and a series of structure-activity relationships could be established upon theirin vitro assays: antioxidant activity, α-glucosidase inhibition and antiproliferative activity against six human tumor cell lines: A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon). For the antiradical activity, selenium atom and 2 or 3 phenolic hydroxyl groups proved to be essential motifs; remarkably, the compound with the most potent activity, with a trihydroxyphenyl scaffold (EC50 = 4.87 ± 1.57 μM) was found to be stronger than natural hydroxytyrosol, a potent antioxidant present in olive oil (EC50 = 13.80 ± 1.41 μM). Furthermore, one of the thiosemicarbazones was found to be a strong non-competitive inhibitor of α-glucosidase (Ki = 9.6 ± 1.6 μM), with an 8-fold increase in activity compared to acarbose (Ki = 77.9 ± 11.4 μM), marketed for the treatment of type-2 diabetes. Most of the synthesized compounds also exhibited relevant antiproliferative activities; in particular, seleno derivatives showed GI50 values lower than 6.0 μM for all the tested cell lines; N-naphthyl mono- and dihydroxylated derivatives behaved as more potent antiproliferative agents than 5-fluorouracil or cisplatin.

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RSC Advances 2015, 5, 21812-21822 Antileishmanial activity of sp2–iminosugar derivatives Elena M. Sánchez-Fernández, Verónica Gómez-Pérez, Raquel García-Hernández, Jose Manuel García Fernández, Gabriela B. Plata, Jose M. Padrón, Carmen Ortiz Mellet, Santiago Castanys, and Francisco Gamarro

A series of sp2-iminosugar-type glycomimetics bearing S-linked pseudoglycoside substituents (sulfide, sulfoxide and sulfone derivatives) has been synthesized and evaluated as new potential drugs against the protozoan parasite Leishmania, responsible of leishmaniasis, the second most relevant parasitic disease after malaria. All the prepared compounds share a bicyclic 5N,6O-oxomethylidenenojirimycin glycone-like moiety bearing a substitution pattern of configurational complementarity with the natural α-glucosides and incorporate either an n-octyl or n-dodecyl aglycone-like substituent. Not surprisingly, they behaved as potent to moderate competitive inhibitors of α-glucosidase (inhibition constants, Ki, in the range 1.3 to 447 μM). Evaluation of the antileishmanial activity indicated that the dodecyl pseudoglycosides present a significant antiparasitic activity in intracellular amastigotes of Leishmania donovani, the clinically relevant form of the parasite. The antileishmanial effect seems to be associated with the anticancer and proapoptotic activity of the glycomimetics, but not with the α-glucosidase inhibitory efficiency. The (SS)-configured dodecylsulfoxide derivative 4, exhibiting the most favourable activity/toxicity profile, was further assayed in combination treatment with miltefosine, the first oral antileishmanial drug, using the fixed ratio isobologram method. The interaction between derivative 4 and 0.1, 0.2 and 0.3 μM miltefosine was classified as synergistic, showing combination indices of 0.78, 0.76 and 0.80, respectively. Additionally, a miltefosine resistant Leishmania line and the wild-type strain showed similar susceptibility to derivative 4. The results illustrate the potential of sp2-iminosugar pseudoglycosides as promising prototypes for the development of new therapeutic strategies for leishmaniasis.

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Pharmacognosy Journal 2015, 7, 178-181 Flavonoids from Eupatorium illitum and their antiproliferative activities Quírico A. Castillo, Jorge Triana, José L. Eiroa, José M. Padrón, Gabriela B. Plata, Ernesto V. Abel-Santos, Luis A. Báez, Diana C. Rodríguez, Marco A. Jiménez, and María F. Pérez-Pujols

Objective: To isolate the chemical constituents of the aerial parts from Eupatorium illitum, elucidate their structures and evaluate their antiproliferative activity on human cancer cell lines. Materials and Methods: The ethanolic extract of Eupatorium illitum afforded five compounds, which were characterized using spectroscopic techniques and by comparison with data from the literature. Antiproliferative activities of selected isolates were evaluated. Results: The flavonoids Kumatakenin (1), Ermanin (2), 7-methoxy-aromadendrin (3) and Naringenin (4), together with 4-hydroxybenzoic acid (5) were isolated. Compounds 1, 2, 4 and 5 were evaluated for their antiproliferative activity on the human cancer cell lines A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573 (lung), and T-47D (breast) presenting a wide range of bioactivities. In general, best results were observed for 5. Conclusion: Compounds 1-5 are reported for first time from Eupatorium illitum. Isolated phytochemicals show moderate to low antiproliferative activities when evaluated on the aforementioned human cancer cell lines.

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RSC Advances 2015, 5, 6647-6651 A practical, catalytic and selective deprotection of a Boc group in N,Nʹ-diprotected amines using iron(III)-catalysis Juan M. López-Soria, Sixto J. Pérez, J. Nicolás Hernández, Miguel A. Ramírez, Víctor S. Martín, and Juan I. Padrón

A selective, catalytic and practical method for removing a Boc group from several N,Nʹ-diprotected amino acids and amine derivatives using iron(III) salts as sustainable catalysts is described. The process is clean, not needing a purification step. A theoretical study rationalizing the results with several metals is presented.

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Bioorganic & Medicinal Chemistry Letters, 2015, 25, 914–918 A new iridoid, verbascoside and derivatives with inhibitory activity against Taq DNA polymerase Hugo A. Garro, Celina García, Victor S. Martín, Carlos E. Tonn, and Carlos R. Pungitore

DNA polymerases are enzymes that play a crucial role in DNA metabolism such as replication, repair, transcription, recombination, and chromosome segregation during mitosis. Herein we report the isolation of a new iridoid (6-epi-catalpol, 2) and per-O-acetyl-verbascoside (11) from aerial part of Buddleja cordobensis Grisebach (Buddlejaceae). From compound 2, we have obtained eight compounds by chemical transformation. This group of compounds at a concentration of 500 μM was assayed against Taq DNA polymerase. Compound 11 (per-O-acetyl-verbascoside) was the most active with an IC50 of 1.21 ± 0.18 μM; compounds 9, 2 and 8 were strong inhibitors with IC50 values of 5.57 ± 0.70, 21.62 ± 0.22 and 78.13 ± 0.93 μM, respectively. Compounds 11 and 9 could be a leader structures to development new anticancer chemotherapy medicines and a useful tool to investigate DNA polymerase activity.

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Synthesis 2015, 475, 1791-1798 Iron(III)-Catalyzed Prins Cyclization towards the Synthesis of trans-Fused Bicyclic Tetrahydropyrans Sixto J. Pérez, Pedro O. Miranda, Daniel A. Cruz, Israel Fernández, Víctor S. Martín, and Juan I. Padrón

trans-Fused bicyclic tetrahydropyrans have been synthesized through an intramolecular Prins cyclization catalyzed by iron(III). The cyclization process is stereoselective, leading exclusively to an all-cis configuration in the newly generated ring. This useful methodology allows for easy access to a variety of bicyclic ethers present in a wide range of bioactive natural products. Remarkably, the cyclization reaction works well when more challenging aldehydes bearing a functional group, such as a double bond or an acetate, are used. In addition, we present a computational study which rationalizes the results and explains the complete cis stereoselectivity in the newly formed tetrahydropyran ring.

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Journal of Separation Science 2015, 38, 2692-2699 Evaluation of two molecularly imprinted polymers for the solid-phase extraction of natural, synthetic and mycoestrogens from environmental water samples before liquid chromatography with mass spectrometry Javier González-Sálamo, Bárbara Socas-Rodríguez, Javier Hernández-Borges, María del Mar Afonso and Miguel Ángel Rodríguez-Delgado

In this work, we have compared the selectivity of two commercial molecularly imprinted polymers (AFFINIMIP®SPE Estrogens and AFFINIMIP®SPE Zearalenone) for the extraction of 12 estrogenic compounds of interest (i.e. 17α-estradiol, 17β-estradiol, estrone, hexestrol, 17α-ethynylestradiol, diethylstibestrol, dienestrol, zearalenone, α-zearalanol, β-zearalanol, α-zearalenol and β-zearalenol) from different water samples. High-performance liquid chromatography coupled with ion trap mass spectrometry with electrospray ionization was used for their determination. Results showed that although both molecularly imprinted polymeric cartridges were specifically designed for different groups of analytes (natural estrogens like estradiol in the first case and zearalenone derivatives in the second) they nearly have the same extraction performance (with recovery values in the range 65–101%) for the same analytes in Milli-Q water because of the cross-reactivity of the polymer. However, when more complex water samples were analyzed, it was clear that the behavior was different and that the AFFINIMIP®SPE Estrogens showed less cross-reactivity than the other cartridge. Validation of the proposed methodology with both cartridges revealed that the extraction was reproducible and that the final limits of detection of the proposed method were in the low ng/L range.

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Archaeological and Anthropological Sciences 2015, 1-25. Contacts under the lens: Perspectives on the role of microstratigraphy in archaeological research Carolina Mallol and Susan Mentzer Achieving an accurate perception of time and context remains a major challenge in archaeology. This paper highlights the potential benefits of microstratigraphic study to address this goal, drawing on case studies from Lower, Middle, and Upper Paleolithic, Neolithic, and Iron Age archaeological sites. First, we discuss the importance of site formation reconstruction and the ways in which current field methods approach the sedimentary record. Then, we focus on both field identification and high-resolution study of stratigraphic contacts, which are ubiquitous in archaeological deposits. Examples are presented to highlight the role of microstratigraphy in characts, which are ubiquitous in archaeological deposits. Examples are presented to highlight the role of microstratigraphy in characterizing the nature of contacts and their significance for archaeological interpretation. A microstratigraphic approach is especially useful for distinguishing between contacts that originate from changes in depositional processes and contacts that form as a result of post-depositional processes such as pedogenesis, diagenesis, or burning. Further examples show how “invisible” anthropogenic surfaces and different kinds of occupation deposits can come to light at a microscopic scale of observation. Finally, we illustrate cases in which what appeared to be sterile layers in the field yielded anthropogenic elements. In the end, we discuss how archaeological projects might incorporate microstratigraphic analyses and their results within broader research frameworks that prioritize site formation process reconstruction.

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Manual de Micromorfología de suelos y técnicas complementarias, Loaiza, J.C. et. al. Eds, Institución Universitaria Pascual Bravo 2015, 321-352. Aplicaciones en Geoarqueología (Capítulo 10) Carolina Mallol En este capítulo se esbozan algunas pautas metodológicas para la práctica de la micromorfología geoarqueológica, así como algunos ejemplos de su aplicación.

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Quaternary Science Reviews 2015, 111, 81-93. Neanderthal firewood management: evidence from Stratigraphic Unit IV of Abric del Pastor (Eastern Iberia) Paloma Vidal, Cristo Hernández, Bertila Galván and Carolina Mallol This paper presents anthracological data from Abric del Pastor (Alcoi, Spain), a Middle Paleolithic rock shelter site. Analysis of 1077 wood charcoal remains from Stratigraphic Unit IV (S.U. IV), collected within archaeological combustion structures and from loose sediment outside of structures, allowed us to characterise the local landscape, as well as to approach the interaction between Neanderthal groups and their local environment. Taxonomic identification suggests that firewood was gathered from nearby sources, with predominance of juniper (Juniperus sp.) followed by thermophilous shrubby taxa. Additional analysis focussing on post-depositional processes affecting charcoal have shown features indicative of biodegradation and mechanical action. The results of this study contribute significant anthracological data towards our understanding of Late Pleistocene Mediterranean landscapes and Neanderthal forest management in this region.

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Settlement Dynamics of the Middle Paleolithic and Middle Stone Age. Tübingen Publications in Prehistory 2015, Vol. IV, 361-382 Insights into Middle Palaeolithic Settlement Patterns: The Palimpsest Problem Jorge Machado, Cristo Hernández and Carolina Mallol Dissecting archaeological palimpsests with the aim of identifying prehistoric occupation episodes and explaining settlement dynamics is not an easy task. However, current high temporal resolution studies focused on Eurasian Middle Paleolithic archaeosedimentary records are starting to provide interesting information in this direction. Here, we review data gathered from a sample of 47 case studies from23 sites, highlighting the main analytical difficulties for the study of settlement dynamics. We do this from a research perspective concerned with the archaeological identification of temporal markers and with the aim of exploring plausible methodological options for an archaeological research agenda that holds the single occupation episode as the basic analytical unit to interpret past human behavior. Our study sample reveals a growing interest in the pursuit of single occupation episode identification, although most of the given contributions show a certain degree of ambiguity regarding estimates of the number of occupation episodes and their relative duration. In our view, a feasible solution to this shortcoming is to carry out more systematic microstratigraphic analyses in combination with other sources of behavioral information, focusing on the effective integration of information derived from macro- and micro-scale data sets.

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Sensors 2015, 15, 9179-9188 Measuring the Contractile Response of Isolated Tissue Using an Image Sensor David Díaz-Martín, José Gerardo Hernández-Jiménez, Manuel Rodríguez-Valido and Ricardo Borges

Isometric or isotonic transducers have traditionally been used to study the contractile/relaxation effects of drugs on isolated tissues. However, these mechanical sensors are expensive and delicate, and they are associated with certain disadvantages when performing experiments in the laboratory. In this paper, a method that uses an image sensor to measure the contractile effect of drugs on blood vessel rings and other luminal organs is presented. The new method is based on an image-processing algorithm, and it provides a fast, easy and non-expensive way to analyze the effects of such drugs. In our tests, we have obtained dose-response curves from rat aorta rings that are equivalent to those achieved with classical mechanic sensors.

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Behavioural Brain Research 2015, 278, 98-106 Mice lacking chromogranins exhibit increased aggressive and depression-like behaviour Daniel Pereda, Marta R. Pardo, Yezer Morales, Natalia Dominguez, Maria Rosa Arnau, Ricardo Borges

Chromogranins are acidic proteins; both chromogranins A and B constitute the main protein component in the vesicular matrix of large dense core vesicles. Chromogranins are a natural source of peptides with different physiological activities that have been associated with vascular and neurological diseases. We have used three different genetic mutant models of mice lacking chromogranin A, chromogranin B and both all on the same C57BL/6J background, to characterize the physiological roles of these proteins using metabolic, cardiovascular and behavioural tests. In mice from 3 to 18 months of age, the lack of any chromogranin promoted age-dependent hypersensitivity to insulin, while the lack of both chromogranins provoked progressive lack of response to stress, as restriction did not promote tachycardia in old mice. Moreover, the lack of chromogranin B produced a depressive-like and aggressive phenotype, while the lack either or both chromogranins increased barbering behaviour. In addition, we observed no effects on light-dark box or RotaRod tests. Mice lacking chromogranin B exhibited lower exploratory activity. Based on this extensive phenotyping with more than 2800 mice, these findings support roles of chromogranins, or the peptides derived from them, in the control of aggressive behaviour along with changes in their metabolic profile beyond their previously described activities in the secretory pathway.

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Phytochemistry 2015, 117, 245-253 Sesquiterpenes, flavonoids, shikimic acid derivatives and pyrrolizidine alkaloids from Senecio kingii Hook Liliana Ruiz-Vásquez, Matías Reina, M. López-Rodríguez, Cristina Giménez, Raimundo Cabrera, Pedro Cuadra, Víctor Fajardo, Azucena González-Coloma

Twenty-four compounds including eleven eremophilanolides (1–11), one eremophilane (13), five shikimic acid derivatives (14–18), six flavonoids (19–24), and the macrocyclic unsaturated pyrrolizidine alkaloid integerrimine (25) were isolated from Senecio kingii, an endemic species from the Magallanes Region (Chile). Compounds 3, 5, 6, 8–11 and 13–18 have not been previously reported as natural products. Their molecular structures were determined by NMR spectroscopic analysis and comparison with published NMR data. An X-ray-analysis of compound 3 has been performed. Their insecticidal and antifungal activities were tested, being compound 3 the strongest insect antifeedant. Compounds 6, 9 and 18 were moderate antifungals.

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Natural Product Report 2015, en prensa Applications of Isothermal Titration Calorimetry as a Powerful Tool to Study Natural Product Interaction Oliver Callies & Antonio H.D.

Over the past twenty-five years, isothermal titration calorimetry (ITC) has become a potent tool for the study a great variety of molecular interactions. This technique is able to provide a complete thermodynamic profile of an interaction process in a single experiment, with a series of advantages in comparison to other comparable techniques, such as less amount of sample or no need of chemical modification or labelling. It is thus not surprising that ITC has been applied to study the manifold types of interactions of natural products to get new insights into the molecular key factors implied in the complexation process of this type of compounds. This review provides an overview over the applications of ITC as a potent tool to investigate interactions of natural products with proteins, nucleic acids, oligosaccharides, and other types of receptors. The examples have been selected depending on the impact that this technique had during the investigation and revision of the interactions involved in the bioactivity of a compound, lead optimization or technical applications.

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Journal of Structural Chemistry 2015, 56, 1563-1571 Halide Copper(II) complexes of aromatic n-donor containing ligands: structural, magnetic and reactivity studies A. Aguirrechu-Comerón, J. Pasán, J. González-Platas, J. Ferrando-Soria, and R. Hernández-Molina

The preparation of four new copper(II) complexes with different N-donor ligands [CuBr2(2- benzylpyridine)2] (1), [CuBr2(2-benzylpyridine)(2,2ʹ-bipyridine)]·H2O (2), [CuBr2(3-methyl- 2-phenylpiridine)2] (3), [Cu(picolinate)2]·KI (4) from is described. During the preparation of compound 4 The complexes were characterized by elemental analyses, IR spectroscopy and crystallographic studies. Single crystal X-ray diffraction analysis of the complexes reveals their monomeric penta- and tetracoordinated nature. For all compounds, the copper(II) present a common square planar coordination except for compound 2 which is five coordinated in a quasi-square pyramidal configuration with τ of 0.29. The Cu–N distances for these compounds are in the range of 1.959(4)-2.041(3) Å, Cu–O distance was 1.961(3) Å and Cu–Br distances were in the range of 2.4052(4)- 2.4381(6) Å for the square base configuration while for apical distance it was 2.6745(7) Å. Magnetic properties have been investigated for all compounds in the temperature range 2-300 K. Compound 1 shows weak antiferromagnetic intermolecular interaction.

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Chemical Communications 2015, en prensa Radical C-H arylations of (hetero)arenes catalysed by gallic acid Marcelle Dayana Perretti, Diego Manuel Monzón, Fernando R. Pinacho Crisóstomo, Victor S. Martin, and Romen Carrillo

Gallic acid efficiently catalyses radical arylations in water–acetone at room temperature. This methodology proved to be versatile and scalable. Therefore, it constitutes a greener alternative to arylation. Moreover, considering that gallic acid is an abundant vegetable tannin, this work also unleashes an alternative method for the reutilisation of bio-wastes.

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Arabian Journal of Chemistry 2015, en prensa Modular total syntheses of thymifodioic/incanic acids Sergio J. Álvarez-Méndeza, J. Roberto Saad, Carlos E. Tonn, Víctor S. Martín, and Celina García

The first total synthesis of the bioactive natural product 2,6-(E,E)-thymifodioic acid, also called incanic acid, and its stereoisomers is described. A unified, iterative and modular strategy was envisioned, achieving the synthesis of the goals products after five reaction steps in an overall yield ranging from 8% to 16%. The key step is a non-expensive easy to perform Horner–Wadsworth–Emmons condensation.

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Chemical Communications 2015, en prensa The Evans Aldol–Prins cyclization: a general and stereoselective method for the synthesis of 2,3,4,5,6-pentasubstituted tetrahydropyrans Sergio J. Álvarez-Méndez, Celina Garcíaa and Víctor S. Martín

A general and stereoselective method to synthesize 2,3,4,5,6-pentasubstituted tetrahydropyrans in three steps starting from three different aldehydes is described. Key substrates β,γ-unsaturated N-acyloxazolidin-2-ones were subjected to an “Evans Aldol–Prins” protocol to generate five σ-bonds and five stereocenters in only a one-pot process with yields up to 60% and excellent stereoselectivities.