Natural Products As Lead Compounds for Drug Development. Part I: Synthesis and Biological Activity of a Structurally Diverse Library of Curcumin Analogues
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Natural Products as Lead Compounds for Drug Development. Part I: Synthesis and Biological Activity of a Structurally Diverse Library of Curcumin Analogues. Part II: Synthesis of Novel Sterol Natural Products and Related Analogues as Antileishmanial Agents. DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Dalia Abdelhamid Sayed Abdelhamid Graduate Program in Pharmacy The Ohio State University 2011 Dissertation Committee: Professor James R. Fuchs, Advisor Professor Pui-Kai Li, Advisor Professor Karl A. Werbovetz Copyright by Dalia Abdelhamid Sayed Abdelhamid 2011 Abstract Natural products have served as an effective source of drugs and drug leads throughout history. In part, this is due to the unique structures and the well-defined stereochemistry found in these compounds which allow them to interact selectively with biological target molecules. Unfortunately, most natural products themselves are not suitable for administration as drugs. Chemical synthesis, however, can be employed to study and address some of these shortcomings through manipulation of pharmacological properties, structure activity relationship studies, and the preparation of compounds for mechanistic studies by molecular biologists. In this thesis, an overview of the role of natural products is presented in order to set the stage for two current drug discovery and development studies which are based on natural product leads. The first project involves the development of a library of curcumin analogues. This effort was initially directed simply at the development of more effective anticancer agents based on the curcumin scaffold. As the project evolved, however, it became clear that a fairly comprehensive library of structurally diverse analogues may be useful for the identification of new leads which could affect other disease states or biological targets. The second project involves the isolation and development of novel compounds for the treatment of leishmaniasis, a parasitic disease. In this case, a short ii synthetic route was developed to give access to the scaffold of the natural products isolated from a Mexican plant. Based on this strategy, a number of analogues have been produced which have helped to define the structure-activity relationship of this class of molecules. iii Dedicated to my Parents iv Acknowledgments I would like to extend my great praise for God; to fill the heavens and earth and everything in between, for blessing me with all the gifts and all the people to support me to achieve this degree. No words can express my sincere gratitude to my parents, who I owe everything I achieved throughout my life, for their continuous love, care, and support. I would like to express my appreciation to all the efforts and sacrifices my husband, Haysam, has endured, and for the endless love, care, patience, understanding, and support he has been giving to me. His belief in me has always driven me forward. Also I would like to thank my two sweet boys Yousof and Mohamad for making me stronger through their pure souls and love. I have also to acknowledge the strong emotional support I received from my sisters, brothers, mother in-law, and sister in-law (Dr. Hala). I would like to acknowledge my advisors Dr. James R. Fuchs and Dr. Tom Li for their genuine guidance and support. I would like to thank Dr. Fuchs for the excellent training I received in his laboratory to make me a better chemist. I want also to express my v appreciation for his inspiration and assistance and to acknowledge his dedication to reach perfection in everything. I am also grateful to Dr. Li for all his supportive care and encouragement, especially in the hard times. I would like to thank him for helping me pursue my goals. I would like also to thank the entire faculty in the Division of Medicinal Chemistry and Pharmacognosy for excellent and enthusiastic teaching, and for providing help and advice. I would like specifically to thank Dr. Werbovetz for being a member of my candidacy and dissertation committee, and for all the encouragement he has given to me. I would like to sincerely thank Dr. Nivedita Jena for her continuous help, support, and all the fruitful discussions and suggestions to improve my laboratory skills. I want to thank all my coworkers in Dr. Fuchs and Dr. Li’s laboratories (Eric Schwartz, John Etter, John Woodard, Mike Corcoran, Pratiq Patel, Sam Boakeye, Nicholas Regan, and Deepak Bhasin) for all the help they had provided. Finally I would like to acknowledge my former Egyptian Professors: Mohamad Alzahaby Saber Barakat, Ehab Fetouh, Mohy Makady, and Alaa Shawky for their tremendous help, and encouragement to achieve my goals, and for their belief in me. vi Vita 2000................................................................B.S. Pharmacy, Cairo University, Egypt 2001-2002…………………………………..Researcher; The National Organization of Drug Control and Research, Cairo, Egypt 2003-2005…………………………………..Instructor, College of Pharmacy, Minia University, Egypt 2006……………………………………… Graduate Teaching Assistant, Chemistry Department, SUNY Albany 2007-2011………………………………… Graduate Egyptian Scholar, College of Pharmacy, The Ohio State University 2009................................................................M.S. Pharmacy, The Ohio State University Publications 1- Fuchs, J.R.; Pandit. B.; Bhasin, D.; Etter, J.P.; Regan, N.; Abdelhamid, D.; Li, C.; Lin, J.; Li, P.K. Structure-activity relationship studies of curcumin analogues. Bioorganic and Medicinal Chemistry Letters 2009, 19(7), 2065-2069. 2- Bill, M. A.; Fuchs, J.R.; Li, C.; Yui, J.; He, L.; Mitchell, A.P.; Bakan, C.; Benson, D. M.; Kulp, S. K.; Scwartz, E.;Abdelhamid, D.; Lin, J.; Hoyt, D. G.; Fossey, S. L.; Young, G. S.; Carson, W. E.; Li, P.K.; Lesinski, G. B. The small molecule curcumin analog FLLL32 induces apoptosis in human melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity inhibition. Molecular Cancer 2010, 9, 165. Fields of Study Major Field: Pharmacy vii Table of Contents Abstract ............................................................................................................................... ii Dedication ........................................................................................................................... ii Acknowledgments............................................................................................................... v Vita .................................................................................................................................... vii List of Tables ................................................................................................................... xiii List of Figures ................................................................................................................... xv List of Abbreviations ....................................................................................................... xxi Chapter 1: Natural products as lead compounds for drug development ........................... 1 1.1. Introduction .................................................................................................................. 1 1.2. Natural products-based drug discovery ...................................................................... 3 1.2.1. Historical perspective ............................................................................................... 3 1.2.2. The process of drug discovery ............................................................................... 10 1.2.3. Properties of natural products ................................................................................ 13 1.2.4. Synthetic modification of natural products ............................................................. 17 1.3. Natural products and the future of drug discovery ................................................... 20 Chapter 2: Curcumin: A pleiotropic natural product ...................................................... 22 viii 2.1. Introduction ............................................................................................................... 22 2.2. Biological activity of curcumin ................................................................................ 25 2.2.1. Anti-inflammatory activity .................................................................................... 26 2.2.2. Antioxidant activity ............................................................................................... 26 2.2.3. Cardioprotective acitvity ........................................................................................ 28 2.2.4. Antiparasitic activity .............................................................................................. 31 2.2.4.1. Antimalarial activity ........................................................................................... 31 2.2.4.2. Antileishmanial activity ...................................................................................... 32 2.2.5. Chemotherapeutic and chemopreventive activity .................................................. 32 2.2.5.1. Curcumin inhibits activation of numerous transcriptional factors ...................... 34 2.2.5.2. Curcumin inhibits inflammatory cytokines ....................................................... 38 2.2.5.3. Curcumin inhibits the activity of multiple protein kinases ................................. 38 2.2.5.4.