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Design, Synthesis, and Structure-Activity Relationship Investigation of 3’,4’-Disubstituted Pyranochromone Derivatives with Diverse Biological Activities

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Design, Synthesis, and Structure-Activity Relationship Investigation of 3’,4’-Disubstituted Pyranochromone Derivatives with Diverse Biological Activities DESIGN, SYNTHESIS, AND STRUCTURE-ACTIVITY RELATIONSHIP INVESTIGATION OF 3’,4’-DISUBSTITUTED PYRANOCHROMONE DERIVATIVES WITH DIVERSE BIOLOGICAL ACTIVITIES Ting Zhou A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Eshelman School of Pharmacy. Chapel Hill 2010 Approved by Kuo-Hsiung Lee, PhD (Advisor) Kenneth F. Bastow, PhD Jian Liu, PhD Qian Shi, PhD Chin-Ho Chen, PhD i ©2010 Ting Zhou ALL RIGHTS RESERVED ii ABSTRACT TING ZHOU: DESIGN, SYNTHESIS, AND STRUCTURE-ACTIVITY RELATIONSHIP INVESTIGATION OF 3’,4’-DISUBSTITUTED PYRANOCHROMONE DERIVATIVES WITH DIVERSE BIOLOGICAL ACTIVITIES (Under the direction of Kenan Professor Kuo-Hsiung Lee) The overall goals of this research are to design and synthesize novel 3’,4’- disubstituted pyranochromone derivatives, to evaluate their anti-HIV activity and chemosensitizing potency, to elucidate structure-activity relationships (SAR), and to discover novel chemical entities. 3’R,4’R-Di-camphanoyl-khellactone analogs (DCKs) was first identified in our laboratory with high anti-HIV activity against wild-type HIV strain early in 1994. Using SAR-directed strategy, 3’R,4’R-di-camphanoyl-pyranochromone analogs (DCPs) were synthesized and evaluated in a continuing study, which showed high potency against both wild-type and multi-RT inhibitor-resistant strains. Mechanism study of DCK and its derivatives suggested that the compounds target HIV-RT in a unique way, by inhibiting its DNA-dependent DNA polymerase activity. A microwave-assisted one-pot reaction was first developed in our study and successfully applied in the preparation of 2’,2’-dimethyl-chromone motifs which were iii key intermediates in DCK and DCP derivatives. The highly efficient microwave synthesis shrinked the reaction time over 12-fold with much higher yield than traditional heating system previously reported. Utilizing the optimized synthesis method, novel DCP analogs were designed and synthesized to further explore functionality requirements on the pyranochromone ring and to improve water solubility. SAR studies led us identified 5-alkyl-DCPs (98, 102) with increased efficacy against both wild-type and drug- resistant HIV strains. Simultaneously, novel DCPs (98, 115) also presented 5- and 10-time higher water-solubility than 2-EDCP (69). Furthermore, we explored the interaction between the planar ring and the binding pocket by constructing a tri-aryl-conjugated system, pyranoxanthones (DCXs). DCX and its analogs maintained and even increased the π-π stacking interaction with the residues inside the binding pocket. Several DCX analogs (131, 135, 144) increased anti-HIV potency against both virus strains and six analogs exhibited improved therapeutic index (TI) compared to the control 2-EDCP (69). Finally, we discovered that 3’,4’-disubstituted pyranochomone (DSP) analogs showed strong potential to reverse multi-drug resistance (MDR) in cancer cell line. A SAR study were established and three DSP analogs (194, 197 and 204) fully resolved vincristine (VCR) resistance in KB-Vin cancer cells, which are over 2-fold more potent than verapamil, a prototype chemosensitizer. Preliminary mechanism study revealed that the chemosensitizing activity of DSP analogs results from the inhibition of cellular P-glycoprotein (P-gp) function. iv DEDICATION To my husband Kwun Wah for his unlimited love and support throughout my graduate school. To my parents for their constant encouragement of my study and career decisions. Thank you. v ACKNOWLEDGEMENTS First, I would like to extend my deepest gratitude to my mentor, Dr. Kuo- Hsiung Lee for all his continuous support during my graduate studies. I am especially grateful for his dedication to teaching me how to think, troubleshoot, and write like a scientist. I am especially grateful to the members of my doctoral committee: Dr. Kenneth F. Bastow, Dr. Jian Liu, Dr. Qian Shi, and Dr. Chin-Ho Chen for their helpful advice and guidance over the past several years. Their expertise and constructive advice have enabled my projects to progress as smoothly as I could imagine. I am especially thankful to Dr. Qian Shi for generously sharing her experience with me and help for me, to Dr. Chin-Ho Chen, Dr. Li Huang, Phong Ho for their contribution to anti-HIV test, to Dr. Kenneth F. Bastow, Chin-Yu Lai, and Dr. Emika Ohkoshi for their guidance and help in cytotoxicity assay, and to Dr. Hao Zhu for his kind help on molecular modeling study. I am very grateful to Dr. Susan Morris-Natschke for her great help for the preparation of papers and this dissertation. Finally, I would also like to thank both current and former members of the NPRLs for their contributions to this work. Their kindness and friendliness have made my time in the lab very enjoyable. In particular, I am indebted to Dr. Kyoko Nakagawa-Goto and Dr. Donglei Yu for their many helpful scientific discussions. vi TABLE OF CONTENTS LIST OF TABLES ..................................................................................................... xii LIST OF FIGURES ................................................................................................. xiii LIST OF SCHEMES ................................................................................................. xv LIST OF SYMBOLS AND ABBREVIATIONS ......................................................... xvii Chapter 1. HIV/AIDS and Treatments ................................................................. 1 1.1 Overview of Aquired Immunodeficiency Syndrome (AIDS) ................. 1 1.2 HIV ...................................................................................................... 2 1.2.1 Structure of HIV-1 ..................................................................... 3 1.2.2 Replication Cycle of HIV-1 ........................................................ 6 1.3 Current Anti-retroviral Drugs ................................................................ 9 1.4 Current Retroviral Therapy and Its Issues ......................................... 16 1.5 References ........................................................................................ 18 Chapter 2. Plant-derived Natural Coumarins and Derivatives as Potent Anti- HIV Agents ....................................................................................... 23 2.1 Introduction ........................................................................................ 23 2.2 Recent Advances in Coumarins as Anti-HIV Agents ......................... 24 2.3 Modification of Suksdorfin ................................................................. 25 2.3.1 Modification of Dihydroxypyrano 3’,4’ Positions ..................... 26 vii 2.3.2 Modification of Substitutions on Khellactone .......................... 28 2.3.3 Development of Bio-isosteres of DCK Analogs ...................... 30 2.3.4 Development of Pyranochromone Derivatives (DCPs) as Novel Anti-HIV Agents ............................................................ 31 2.4 Studies on Mechanism of Action ....................................................... 33 2.4.1 Structure of HIV-1 RT ............................................................. 33 2.4.2 Mechanism Study of DCK and Its Derivatives ........................ 34 2.5 Conclusions ....................................................................................... 37 2.6 References ........................................................................................ 39 Chapter 3. Efficient Microwave-assisted One-pot Preparation of Angular 2,2-Dimethyl-2H-chromone Containing Compounds ................... 42 3.1 Introduction ........................................................................................ 42 3.2 Results .............................................................................................. 44 3.3 Discussion and Conclusions .............................................................. 51 3.4 Experimental Section ......................................................................... 52 3.5 References ........................................................................................ 58 Chapter 4. Design, Synthesis, Molecular Modeling and Structure-activity Relationship of Novel Dicamphanoyl-2’,2’-dimethyldihydro- pyranochromone (DCP) Analogs as Potent Anti-HIV Agents ...... 59 4.1 Introduction ........................................................................................ 59 4.2 Results and Discussion ..................................................................... 62 4.2.1 Chemistry ............................................................................... 62 4.2.2 Biological Evaluation .............................................................. 69 4.2.3 Water Solubility (WS) Analysis ............................................... 73 viii 4.2.4 Molecular Modeling ................................................................ 75 4.2.4.1 Partial Least Square (PLS) QSAR ............................ 75 4.2.4.2 Pharmacophore Analysis .......................................... 76 4.3 Conclusions ....................................................................................... 77 4.4 Experimental Section ......................................................................... 78 4.4.1 Chemistry .............................................................................. 78 4.4.2 HIV-1 Infectivity Assay ........................................................... 96 4.4.3 Cytotoxicity Assay
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