UNIVERSITITEKNOLOGI MARA

SYNTHESIS OF HALOGEN- SUBSTITUTED STYRYL LACTONES AND THEIR CYTOTOXIC ACTIVITY

AGAINST T-JURKAT CELL LINE

NIK SALMAH BINTI NIK SALLEH

Thesis submitted in fulfilment of the requirements for the degree of

Master of Science

Faculty of Pharmacy

March 2014

AUTHOR’S DECLARATION

I declare that the work in this thesis/dissertation was carried out in accordance with the regulations of Universiti Teknologi MARA. It is original and is the result of my own work, unless otherwise indicated or acknowledged as referenced work. This thesis has not been submitted to any other academic institution or non-academic institution for any degree or qualification.

I, hereby, acknowledged that I have been supplied with the Academic Rules and Regulations for Post Graduate, Universiti Teknologi MARA, regulating the conduct of my study and research.

Name of Student :Student I.D. No.Programme :Faculty :Thesis :

Signature of Student :Date

Nik Salmah binti Nik Salleh 2008264844Master of Science (PH 780)PharmacySynthesis of Halogen-substituted Styryl Lactones and Their Cytotoxic Activity Against T-Jurkat Cell Line

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March 2014

ABSTRACT

Styryl lactones are small organic compounds that possess interesting biological properties. A study was done in order to synthesise halogen substituted styryl lactones as only few of these derivatives have been reported. A new synthetic route has been established which consists of three steps only. Commercially available 3,4-dihydro-2//-pyran-2-methanol was used as starting material and subjected to Swem oxidation to provide the corresponding aldehyde. This reaction was conducted at -78 °C in the presence of dimethyl sulfoxide (DMSO), oxalyl chloride (COCl)2 and triethylamine (EtjN). Phosphonium salts were synthesised through microwave irradiation. These phosphonium salts were subjected to a base to yield Wittig reagents. Wittig reactions were performed in a -40 °C bath by using tetrahydrofuran (THF) and sodium bis(trimethylsilyl)amide (NaHMDS) leading to (Z)-precursors of halogen- substituted styryl lactones. The oxidation of the styryl lactone precursors with tert-butyl hydroperoxide (/buBOOH) and pyridinium dichromate (PDC) in dichloromethane (CH2CI2) at -40 °C yielded the targeted products as well as two by-products with overall yields of main product ranging from 45 % to 67 %. The final products were purified by both column chromatography and preparative layer chromatography (PLC). The structures of the synthesised compounds were confirmed by nuclear magnetic resonance (NMR) and mass spectrometry analyses. The cytotoxic activity of the six final compounds was tested on E6.1 Jurkat-T cell line. All targeted compounds showed encouraging cytotoxic activity with IC50

ranging from 26 % to 120 % of that goniothalamin.

ACKNOWLEDGEMENT

I would like to take this opportunity to express my greatest appreciation to my supervisor, Prof. Dr. Jean-Frederic Faizal Weber Abdullah for his patient guidance, assistance and support during my journey to finish this research. Also, my special thanks to my co­supervisors, Dr. Mohd Zulkefeli Mat Jusoh and Dr. Motiur Rahman for their help and endless encouragement.

My completion of this project could not have been accomplished without the support of my colleagues, Suraya Zulkepli and Mazlin Mohideen. To my lab-mates especially Mohd Zaimi Mohd Noor and Ratni Suriyani Jalal, thank you so much for your kind help. Also, I would like to acknowledge Dr. Chan Kok Meng and Leong Li Hui from Biocompatibility and Toxicology Lab, Faculty of Health Sciences, UKM for their collaboration in conducting cytotoxic activity of synthesised compounds. My grateful thanks are also extended to the authority of Atta-ur- Rahman Institute for Natural Product Discovery, UiTM for providing me with a comfortable and good facility to complete this research.

Finally, my deepest gratitude goes to my husband, Ahmad Junaidi Baharuddin. Your encouragement when the times got rough is much appreciated. Also, my heartfelt thanks go to my parents, my parents-in-law and my siblings for their tremendous support throughout my studies.

TABLE OF CONTENTS

AUTHOR’S DECLARATIONPage

ii

ABSTRACT iiiACKNOWLEDGEMENT iv

TABLE OF CONTENTS V

LIST OF TABLES ix

LIST OF FIGURES X

LIST OF SCHEMES xii

LIST OF ABBREVIATIONS xiv

CHAPTER ONE: INTRODUCTION 11.1 Background 1

1.2 Problem Statements 2

1.3 Objectives of the Research 3

1.4 Scope of the Research 3

CHAPTER TWO: LITERATURE REVIEW 42.1 Natural Styryl Lactones 5

2.2 Chemical Synthesis of Styryl Lactones 132.2.1 Chiral Precursor Prepared with the Aid of a Microorganism 132.2.2 Aldol Reaction 14

2.2.3 Diastereoselective Oxidation and Reduction Sequence 15

2.2.4 Cosford Cross-coupling Protocol (Allylation) 16

2.2.5 P-Lactone Route to a,P-Unsaturated 8-Lactones 17

2.2.6 Allylboration-esterification Ring-closing Metathesis Reaction 172.2.7 Lemieux-Johnson Oxidative Cleavage, Enantioselective Keck Allylation,

Ring-closing Metathesis and Wittig Olefination 182.2.8 Pseudomonas (AK) Lipase and Selective Hydrogenation with Lindlar Catalyst 19

2.2.9 Sulfoxide-modified Julia Olefination 20

v