Cyclodextrins and their Applications

Cyclodextrins and their ApplicationsByGeethika (2012B2PS619G)Sai Kulkarni (2012B2A4640G)Priyanka Bedarkar (2012B2A7586G)

CyclodextrinsCyclic oligosaccharides

Cage molecules with a stable hydrophobic cavity that can trap or encapsulate other molecules

Used in food, pharmaceutical, drug deliveryand chemical industries, agriculture and environmental engineering.

Discovery: 18911911The Period of Doubt: 19111935Reaching Maturity: 19351950Exploration: 19501970 The Period of Application: From 1970 until NowImportant Periods in Cyclodextrin History

Antoine Villiers During experiments on the degradation and reduction of carbohydrates under the action of ferments, Villiers noted the formation of unwanted crystals with particular properties; he named it cellulosine.Under certain conditions, potato starch can ferment to mainly yield dextrins Franz Schardinger Isolated pure fractions: obtained a maximum yield of 30% crystalline dextrins from starch.First researcher to describe the fundamental properties of these dextrins, therefore known as the Founding Father of cyclodextrin chemistry.

Discovery (1891-1911)structure of the dextrins had not yet been established Hans Pringsheim depolymerized the Schardinger dextrins into polyamyloses and studied the relationship between these polyamyloses and the amylose and amylopectin moleculesDiscovered in 1930 that crystalline dextrins and their acetate derivatives tended to form complexes with various organic compoundsPaul Karrerrst to propose that dextrins are composed of maltose units only joined by (14) glucosidic linkagesHowever, just like Schardinger and Pringsheim, Karrer failed to elucidate the cyclic structure of the dextrins

The Period Of Doubt: 19111935

Karl Johann FreudenbergIn 1935, he described a method for the synthesis of Schardinger dextrins with high purity and, using a cryoscopic method for the determination of molecular weights, reported (erroneously) the number of glucose units that the CDs contained: ve for -dextrin and six for -dextrinobserved that enzymatic hydrolysis gave no trace of a sugar unit other than D-glucose, and methylation studies failed to reveal the presence of any D-glucose units.suggested, for the rst time, the hydrophobicity of the inner surface of the dextrin and noted how dextrins had the ability to accept molecular inclusions in their cavityPrepared pure -dextrins and discovered -dextrins.

Reaching Maturity: 19351950

Dexter Frenchhypothesized that the cryoscopic method used by Freudenberg was inappropriate to determine the molecular weights because the dextrins were of comparatively high molecular weight and were very dicult to free from low molecular weight impuritiesdetermined the molecular weights of - and -dextrins and discovered the exact number of glucose units per dextrin, that is, six and seven, respectivelyshowed that Schardinger dextrins were cyclic oligosaccharidesIn the late 1950s, French and co-workers had established the molecular weight, the exact chemical structure, the dimensions, and the types of bonding in the three cycloamyloses

Friedrich Cramer showed that the main value of CDs resided in their ring structure and their consequent ability to include guest molecules inside their internal cavityshowed that not only can CDs be used as accelerating agents but also as an asymmetric agent.

Exploration: 19501970

Friedrich Cramer

Benito Casu

Myron BenderBenito CasuShowed that 1H NMR and infrared spectroscopy were powerful methods to study the conformations of CDsIR and NMR spectra showed that the C1H bond was equatorial and C1O axial, also conrming the C1 chair conformation of the glucopyranose units.Casu also showed the existence of intermolecular hydrogen bonds contributing to the stabilization of the helical structures

Myron Lee Benderinitiated the era of biomimetic chemistry (including articial enzymes, molecular recognition, and bioinsipired reactivity),works of Bender made the creation of articial enzymes possible

1970sPharmaceutical applications: enhancing the solubility of drugs, and nonionic surfactantsCreation of articial enzymes using CDs1980schromatographic applications and many industrial applications discoverednumerous fundamental studies were done on CDs1990ssynthesis of new supramolecular molecules and materials such as interlocked molecules (catenanes, rotaxanes), scaolds and templates to self-assemble supramolecular architectures, and also in biomimetism. The Period Of Application: From 1970 Until Now

Pharmaceutical Applications of Cyclodextrins

1.Drug solubilization2.Drug stabilization-Sai Kulkarni

Solubility of beta cyclodextrin in water is very low 1.85(g/100ml)High crystal lattice energyIntramolecular hydrogen bondSolubility can be increased by replacing H atom of secondary hydroxyl groups by substitution (alkylation, esterification etc.)

Solubility of cyclodextrins

Relatively strong binding of cyclodextrin moleculesH bonding between secondary oOH grps in moleculeHydrophobic moieties replacing H methylation2/3 rd of hydroxyl groups are methylated has highest solubility but after more methlylation reduces solubility , permethylated derivative has less solubilityHydrophobic cavity enhances drug CD complexationNon covalent interactions12Release of enthalpy rich water molecule from CD cavityVan der Waals interaction(negative H and negative S)Hydrogen bondingHydrophobic interactions(Large positive S)Release of ring strain in CD molecule(specially in case of -cyclodextrin)Changes in solvent surface tensions

Orstan, A.; Ross, J. B. A. J. Phys. Chem. 1987, 91, 2735-2745.Driving forces for drug-CD complex formation :Delta g = delta h T*delta sAlpha CD forms H bonding with water molecule inside its cavity which perturbes cyclic structure and macrocycle, release of water molecule

13

Formation of ternanry complex with cyclodextin molecule, drug molecule and third component.(water soluble polymers , hydroxy acids or salts with basic drugs)Addition of hydroxy acids enhances formation of super complexes and saltsWater soluble polymers increases stability constant

Higuchi, T.; Connors, K. A. In Advances in Analytical Chemistryand Instrumentation; Reilly, C. N., Ed.; Wiley-Interscience: NewYork, 1965; Vol. 4, pp 117-212Method for enhancing complexation :

Aqueous solubility of pure drugMolar substitution on cyclodextrin moleculeCharge on cyclodextrins

Loftsson, T.; Brewster, M. E.; Derendorf, H.; Bodor, N. Pharm.Ztg. Wiss. 1991, 4/136, 5-10.Drug Solubilization :

Cyclodextrin-based multivalent glycodisplays

Cyclodextrin-based multivalent glycodisplays: covalent and supramolecular conjugates to assess carbohydrateprotein interactions A lvaro Martnez,a Carmen Ortiz Mellet*a and Jose M. Garc a Fernandez*b Chem. Soc. Rev., 2013, 42, 4746Multivalent CDs can be considered as hybrid ligandhost molecules bearing two orthogonal recognition domains, namely the glycoligand displayArtificial glycoprotein conjugatesGlycopeptidesSaccharide thin layersSaccharide nano-particlesthe hydrophobic cavityWhat are multivalent CDs?Lectinsare a type of protein that can bind to cell membranes. They are sugar-binding and become the glyco portion of glycoconjugates on the membranes.Lectinsoffer a way for molecules to stick together without getting the immune system involved, which can influence cell-cell interaction.

LectinsSaccharides displayed on the surfaces of cells have been related to a variety of different biological activities, including cell-cell adhesion, protein recognition, pathogen infection, and cancer metastasis.Saccharide-protein interactions, however, are usually too weak to be used as drugs and biomaterials. Interestingly, it is well known that saccharide-protein interactions can be amplified by multivalency, otherwise known as the cluster glycoside effect Why glycoclusters form?Many of the multivalent sugar constructs succeed in emulating the increase in binding affinity towards specific protein receptors encountered in natural systems. Yet, only a few of them can fully mimic the switching between the on and off states and the regulation of the binding intensity after an external stimulus characteristic of carbohydrateprotein binding-mediated processes.

Self-Inclusion into CDActing as switch

Djedani-Pilard and Garca Fernandez et al. conceived a system based on the reversible structure-dependent binding concept by designing conformationally switchable glycoligands that are sensitive to chemical inputs. They exploited the ability of L-tyrosine moieties anchored at a primary position of bCD to undergo self-inclusion of the aromatic ring into the CD cavity. Installing this segment in the bridge connecting the bCD core to a glycodendritic branch, containing either one or two copies of the branched trisaccharide 3,6-di-O-(a-D-mannopyranosyl)-a- D-mannopyranose (Man-tri), led to formation of the corresponding intramolecular complex, in which the external sugars were not accessible to Con A lectin recognition processes. The addition of a guest molecule having strong affinity towards the bCD cavity, e.g. an adamantane derivative, disrupted self-inclusion and activated lectin binding capabilities. Full reversibility of the process was proven by addition of an a,a0-trehalose-based host (cyclotrehalan) that behaved as an adamantane scavenger, restoring the initial state. The involvement of selfinclusion as the key step was supported by spectroscopic evidence as well as by molecular dynamics simulations. Selective replacement of the primary hydroxyl groups in cyclodextrins by halogen (I, Br) represents the most efficient strategy to access homogeneously per-(C-6)-functionalized CD derivatives.The reproducibility and high yield of these transformations have provided an excellent model system to test the suitability of different methodologies towards glycocluster synthesis, which are itemized hereinafter. Moreover, in the resulting jellyfish-type arrangement the wider secondary rim of the CD platform remains open for the entrance of suitable guests to the internal cavity, potentially retaining the capacity for drug encapsulation and delivery.Primary face-anchored jellyfish-type glycoclusters

Eventually, the incorporation of coating sugars on CD platform resulted in additional interactions with an included guest following an induced-fit process that, at its turn, may preorganize the glycotopes for lectin recognition.This accounts for the unexpected high association constants of the amidolactitol-derived bGal conjugate towards both the anticancer drugs doxorubicin (DXR) and PNA lectin Guest-induced mechanism for preorganization of bGal ligands in jellyfish-like heptavalent bCD conjugates proposed by Hattori and co-workersThe above pioneering work already evidenced three important general features of primary face-anchored multivalent CDglycoclusters that make them attractive candidates for site-specific drug delivery, namelyhigh water solubility, an improved binding affinity towards complementary lectins encapsulation capabilities that are retained for guests entering the CD cavity through the secondary rim.Why glycoclusters form?