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Design and Synthesis of Potential Anticancer Agents a Dissertation Design and Synthesis of Potential Anticancer Agents A dissertation presented to the faculty of the College of Arts and Sciences of Ohio University In partial fulfillment of the requirements for the degree Doctor of Philosophy Weihe Zhang November 2010 © 2010 Weihe Zhang. All Rights Reserved. 2 This dissertation titled Design and Synthesis of Potential Anticancer Agents by WEIHE ZHANG has been approved for the Department of Chemistry and Biochemistry and the College of Arts and Sciences by Stephen C. Bergmeier Professor of Chemistry and Biochemistry Benjamin M. Ogles Dean, College of Arts and Sciences 3 ABSTRACT ZHANG WEIHE, Ph.D., November 2010, Chemistry Design and Synthesis of Potential Anticancer Agents (223 pp.) Director of Dissertation: Stephen C. Bergmeier Most cancers mainly rely on glucose as a source of biosynthesis material and energy for their fast growth and proliferation. We proposed inhibiting glucose uptake might kill cancer cells by restricting their energy supply. Based on this hypothesis, we designed and synthesized small molecules which can inhibit the glucose uptake and cell growth in lung cancer line H1299. These small molecules acted as potential novel anticancer agents. First, we designed and synthesized phenolic benzoate esters, from which most compounds displayed mild to good inhibitory activity in glucose uptake and cell growth. The Structure-Activity-Relationship (SAR) was studied by changing different substituents on the core aromatic ring and the pendant aromatic rings, as well as changing the number of hydroxyl groups on the pendant aromatic rings. SAR showed the meta-hydroxyl group played an important role in both inhibitory activity. Due to the instability of the benzoate esters, we designed and synthesized hydrolytically more stable analogs-phenolic ethers, N-linked and S-linked phenolic derivatives. The phenolic ethers showed better inhibitory activity than the N-linked and S-linked phenolic analogs. Finally, the nitro phenolic ether WZB-173 was selected as the lead compound. Approved: _____________________________________________________________ Stephen C. Bergmeier Professor of Chemistry and Biochemistry 4 Dedicated to my wife Junling Yang and my two wonderful daughters Jasmine Hongshun Zhang and Angela Hongli Zhang 5 ACKNOWLEDGMENTS First, I would like to express my deepest gratitude to my academic advisor Professor Stephen C. Bergmeier for his mentorship, guidance, insightful discussions, continuous support, patience and encouragements during the five years of my study at Ohio University. Then I would like to thank Professor Xiaozhuo Chen, one of my dissertation committee members and research collaborators, for his valuable discussions and suggestions during my research. I would also like to thank my dissertation committee members: Professor Mark C. McMills and Professor Shiyong Wu for their valuable discussions and suggestions during my study. Special thanks go to the members of Prof. Bergmeier’s research group both former members (Dr. Junfeng Huang, Dr. Pulipaka B. Aravinda, Dr. Ahbigit Nayek, Ms. Nova Emerald, and Dr. Iwona Maciagiewicz) and present members (Ms. Fang Fang, Dr. George Acquaah-Harrison, Dr. Crina M. Orac, Ms. Susann Krake, Mr. Gregg Wells and Mr. Dennis Roberts) for their useful discussions and building a productive laboratory culture. I would also like to express special thanks to Ms. Yi Liu in Prof. Xiaozhuo Chen’s laboratory for her hard work on testing all the compounds and her valuable discussions on the bioactivity data. I am thankful to the faculty of the Department of Chemistry and Biochemistry, especially Dr. Klaus Himmeldirk, Professor Hao Chen and Dr. Kumar Pichumani as well as the administrative staff of the Department of Chemistry and Biochemistry for their 6 suggestions and support during my study. I also want to thank my friends Dr. Yao Lu, Dr. Dan Wang, Ms. Jingxing Li, Mr. Xiaoxi Ling, Ms. Zhixin Miao, Dr. Yuwu Zhong, Dr. Kun Zhang, Mr. Xiaoyong Lu, Mr. Huaibo Ma, Mr. Haoshuang Wang, Ms. Yan An, Mr. Huamin Li, Ms Yu Cai, Mr. Zhiguo Wang, Mr. Yueran Yan, Dr. Jing He and Ms. Yun Zhang for their friendship. Finally I want to thank my parents, my younger sister and my parents-in-law for their support and encouragement throughout my study and my daily life. Specialty is for my wife, Junling Yang, and two wonderful daughters, Jasmine Hongshun Zhang and Angela Hongli Zhang, for your love, encouragement, patience and sharing life with me. 7 TABLE OF CONTENTS Page ABSTRACT ........................................................................................................................ 3 DEDICATION .................................................................................................................... 4 ACKNOWLEDGMENTS .................................................................................................. 5 LIST OF TABLES .............................................................................................................. 9 LIST OF FIGURES .......................................................................................................... 10 LIST OF SCHEMES......................................................................................................... 13 ABBREVIATIONS .......................................................................................................... 14 CHAPTER 1: INTRODUCTION ..................................................................................... 15 CHAPTER 2: BACKGROUND ....................................................................................... 17 2.1 Warburg Effect ....................................................................................................... 17 2.2 Glucose Metabolism ............................................................................................... 17 2.3 Anticancer Agents ................................................................................................... 21 2.3.1 Known anticancer drugs .................................................................................. 21 2.3.1.1 Alkylating agents ........................................................................................ 21 2.3.1.2 Antibiotics .................................................................................................. 22 2.3.1.3 Antimetabolites .......................................................................................... 24 2.3.1.4 Anti-mitotic agents ..................................................................................... 25 2.3.1.5 Topoisomerase inhibitors ........................................................................... 27 2.3.2 Phenols and polyphenols .................................................................................. 29 2.3.2.1 Antioxidants ................................................................................................ 29 2.3.2.2 Glucose transport (GLUT) inhibitors ........................................................ 31 2.4 Research Design and Significance .......................................................................... 33 CHAPTER 3: DESIGN AND SYNTHESIS OF PHENOLIC BENZOATE ESTERS .... 36 3.1 Design and Synthesis of Phenolic benzoate Esters ................................................. 36 3.1.1 Design and synthesis of 3,4,5-tri-hydroxyl benzoate esters ............................ 37 3.1.2 Design and synthesis of di-hydroxyl benzoate esters ...................................... 48 3.1.2.1 Synthesis of 3, 5-dihydroxyl benzoate esters .............................................. 50 3.1.2.2 Synthesis of 3, 4-dihydroxyl benzoate esters .............................................. 51 8 3.1.3 Design and synthesis of mono-hydroxyl benzoate esters ................................ 58 3.1.3.1 Synthesis of ortho-hydroxyl benzoate esters ............................................. 59 3.1.3.2 Synthesis of para-hydroxyl benzoate esters .............................................. 63 3.1.3.3 Synthesis of meta-hydroxyl benzoate esters .............................................. 68 3.2 Design and Synthesis of Analogs of Phenolic Benzoate Esters ............................. 75 3.2.1 Synthesis of the fluoro-benzoate ester derivatives ........................................... 75 3.2.2 Synthesis of the methoxyl-benzoate ester derivatives ..................................... 80 3.2.3 Other derivatives of phenolic benzoate ester ................................................... 84 3.3 Stability Study on Selected Benzoate Esters .......................................................... 88 3.4 Structure-Activity-Relationship (SAR) .................................................................. 90 CHAPTER 4: DESIGN AND SYNTHESIS OF MORE STABLE ANALOGS ............. 93 4.1 Design and Synthesis of Phenolic Ether Derivatives .............................................. 94 4.2 Design and Synthesis of N-linked Phenolic Derivatives ...................................... 102 4.2.1 Design and synthesis of phenolic amide derivatives ..................................... 103 4.2.2 Design and synthesis of phenolic amine derivatives ..................................... 108 4.2.3 Design and synthesis of phenolic amide/ester derivatives ............................. 113 4.3 Design and Synthesis of S-linked Derivatives ...................................................... 117 4.4 Modification of the Phenolic Ether Derivatives ................................................... 122 4.5 Structure-Activity-Relationship (SAR) ...............................................................
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