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Table of Contents I Synthesis and Evaluation of2,3-Dihydroquinazolinones as Dual Inhibitors of Angiogenesis and Cancer Cell Proliferation Gary Michael Chinigo Monroe, Connecticut B. S., University of Michigan at Ann Arbor, 2000 A Disseltation Presented to the Graduate Faculty of the University of Virginia in Candidacy for the Degree of Doctor of Philosophy Department of Chemistry University of Virginia January 2007 II © Copyright by Gary Michael Chinigo All Rights Reserved January 2007 III Abstract Dual inhibitors of cancer cell proliferation and angiogenesis have recently shown remarkable potential for the clinical treatment of several cancers. Inspired by this success, we have employed traditional medicinal chemistry techniques to develop a 2,3-dihydroquinazolin-4- one lead molecule with promising anti-proliferative and anti-angiogenic activity. These molecules, which we originally derived from thalidomide, have evolved into an extremely effective (sub-nanomolar) prospective drug candidate for the treatment of cancer. Described herein is an account of the many structural modifications made to this lead compound along with the corresponding effects on competitive 3H colchicine displacement from tubulin, microtubule depolymerization, and cytotoxicity toward several human cancer and endothelial cell lines. From these evaluations we were able to design 3rd generation analogs with significantly enhanced potency. Subsequent animal testing suggests these molecules are relatively non-toxic, bio-available, and efficacious at treating tumors in vivo – evidence which supports the possibility of our most active analogs being evaluated clinically. In addition to the SAR studies, we were compelled to develop synthetic methods enabling us to synthesize the enantiomers of these molecules. Exploration of several different approaches eventually led us to a chiral auxiliary based method of synthesis. Preliminary success led to a more thorough exploration of the scope and limitations of this methodology, and ultimately to the synthesis of the R and S enantiomers of both the lead and our most active molecule. Related X- ray crystal structure and biological studies conclusively point to the S isomer as the biologically active enantiomer. Finally, by using molecular modeling in conjunction with all the data gathered thus far, we have developed a hypothesis regarding the likely mode of interaction between tubulin and the molecules in this study. IV Table of Contents Copyright II Abstract III Table of Contents IV List of Figures, Tables, & Schemes VII List of Abbreviations XII Chapter 1: Introduction 1 1.1 Cancer 2 1.2 Tubulin 4 1.3 Angiogenesis 7 1.4 Discovery of Dihydroquinazolinone SC-2-71 13 1.5 Biological Mechanism of Action 18 1.6 Experimental Design 23 1.7 Chapter 1 References 25 Chapter 2: A-Ring Analogs and B-Ring Analogs 35 2.1 Synthesis of A-Ring Analogs 37 2.2 Synthesis of B-Ring Analogs 40 2.3 Biological Evaluation & SAR Conclusions 42 2.4 Chapter 2 References 48 Chapter 3: C-Ring Analogs and D-Ring Analogs 52 3.1 Synthesis of C-Ring Analogs 53 V 3.2 Synthesis of D-Ring Analogs 55 3.3 Biological Evaluation & SAR Conclusions 58 3.4 Chapter 3 References 64 Chapter 4: Third Generation Hybrid Molecule 66 4.1 Synthesis of GMC-5-193 67 4.2 Biological Evaluation 67 4.3 In Vivo Testing 71 4.4 Chapter 4 References 76 Chapter 5: Dihydroquinazolinone Enantiomers 77 5.1 Asymmetric Organolithium Addition 80 5.2 Asymmetric Hydrogenation 83 5.3 Curtius Rearrangement 84 5.4 Chiral Auxiliary 86 5.5 New Methodology – Scope and Limitations 92 5.6 Synthesis of Fourth Generation Hybrid Enantiomers 95 5.7 Biological Evaluation 96 5.8 Chapter 5 References 98 Chapter 6: Molecular Modeling of β-Tubulin 103 6.1 Potential Binding Site 104 6.2 FlexX Docking of Quinazolinones 104 6.3 Correlation with Experimental Data 106 6.4 Preliminary Modeling Conclusions 110 6.5 Chapter 6 References 112 VI Chapter 7: Concluding Remarks 115 Chapter 8: Experimental Section 117 8.1 Materials 117 8.2 Analytical Procedures 117 8.3 Synthetic Procedures 117 8.4 Biological Methods 204 8.5 Molecular Modeling Methods 208 8.5 Chapter 8 References 209 VII List of Figures 1.1A: Major Causes of Death in the US 2 1.1B: Estimated US Cancer Deaths in 2006 3 1.2A: Alpha and Beta Tubulin Sub-units Form Microtubules 4 1.2B: The Organization of Microtubules and Related Structures Within a Cell 5 1.2C: Main Components of the Mitotic Spindle 6 1.3A: Activators and Inhibitors of Angiogenesis 7 1.3B: Diseases Resulting from Abnormal Angiogenesis 8 1.3C: Non-vascularized Tumors Need a Blood Supply to Grow 12 1.3D: Angiogenesis Signals Cause Vascularization 12 1.3E: Inhibiting Angiogenesis Prevents Tumor Growth 12 1.4A: Chemical Evolution of Thalidomide 14 1.4B: NCI 60-Cell Line Screen for SC-2-71 15 1.4C: CAM Assay for SC-2-71 16 1.5A: SC-2-71 Inhibition on Division of HeLa Cells 18 1.5B: SC-2-71 Causes Microtubule Depolymerization on A-10 Cells 19 1.5C: Molecules with Structural Similarities to SC-2-71 20 1.5D: Mechanism of P-Glycoprotein Drug Efflux 21 1.6A: Experimental Design for the SAR Study 23 2A: Structures of Quinazolinone Related Analogs 36 2B: Proposed A- and B- Ring Analogs 37 2.1A: Mechanism of DHQZ Formation 38 VIII 3A: Proposed C- and D- Ring Analogs 52 3.3A: Correlation Plot of HMVEC and HCC-2998 GI50 Values 62 4A: Design of 3rd Generation Drug 66 4.2A: NCI 60-Cell Line Screen of 61 68 4.2B: NCI 60-Cell Line Comparison of SC-2-71 vs. 61 69 4.3A: B-16 Metastatic Melanoma Lung Model of 61 74 5A: Biological Roles of Thalidomide Enantiomers 79 5.1A: Denmark’s Asymmetric Imine Addition 80 5.4A: Putative Anionic Racemization Mechanism 88 5.4B: Chiral Auxiliary-Based Approach to Synthesize the DHQZ Enantiomers 89 5.5A: X-Ray Structure of Diastereomer 76b 94 5.7A: Structure of Taxol vs. 84 97 6.1A: Structural Homology Between Colchicine and Podophyllotoxin 105 6.3A: Compound 84 Docked with Tubulin 107 6.3B: Interactions Between 84 and Various Tubulin Residues 108 6.3C: Cutaway of 23 Docked with Tubulin from Perspective of Biphenyl Axis 109 6.3D: Analog 23 Docked with Tubulin 110 6.3E: SC-2-71 Docked with Tubulin, Overlapped with Podophyllotoxin 110 List of Tables 1.3A: Angiogenesis Inhibitors in Clinical Trials I 10 1.3B: Angiogenesis Inhibitors in Clinical Trials II 10 IX 1.3C: Angiogenesis Inhibitors in Clinical Trials III 11 1.4A: Thalidomide vs. SC-2-71 for Angiogenesis Inhibition 16 1.4B: Antiproliferative Abilities for SC-2-71, 5-FU, and Vincristine 17 2.3A: Microtubule Depolymerization and Tritiated Colchicine Displacement for A- and B- Ring Analogs 43 2.3B: HCC-2998 Antiproliferative Activities of Analogs 1 – 21 45 2.3C: HMVEC Antiproliferative Activities of Analogs 1 – 21 46 3.3A: Microtubule Depolymerization and Tritiated Colchicine Displacement for C- and D- Ring Analogs 59 3.3B: HCC-2998 Antiproliferative Activities of Analogs 22 - 60 60 3.3C: HMVEC Antiproliferative Activities of Analogs 22 – 60 61 4.2A: Microtubule Depolymerization and Tritiated Colchicine Displacement for Analog 61 and Related Compounds 70 4.2B: Antiproliferative Assay of 61 on HCC-2998 Cell Line 70 4.2C: Antiproliferative Assay of 61 on HMVEC Cell Line 70 4.3A: MTD Study of 61 72 4.3B: Relative MTD Values of 61 vs. Some Common Pharmaceuticals 72 4.3C: Estimated Lethal Doses of Some Common Substances 73 5A: Effects of Separate Enantiomers of Some Commercially Available Drugs 77 5.4A: Screen of Several Chiral Auxiliaries 91 5.7A: Antiproliferative Activities of 60, 84, and 87 97 X List of Schemes 2.1A: Synthesis of A-Ring Analogs 1 - 14 39 2.1B: Synthesis of A-Ring Analogs 15 - 17 40 2.2A: Synthesis of Thioamide 18 41 2.2B: Synthesis of Quinazolinones 19 and 20 41 2.2C: Synthesis of Quinoxaline 21 42 3.1A: Synthesis of C-Ring Analogs 22 – 29 54 3.1B: Synthesis of C-Ring Analog 30 54 3.1C: Synthesis of C-Ring Analog 31 55 3.2A: Synthesis of D-Ring Analogs 32 – 55 56 3.2B: Synthesis of D-Ring Analog 56 – 58 57 3.2C: Synthesis of D-Ring Analog 59 - 60 57 4.1A: Synthsis of Analog 61 67 5.1A: Prepration of Chiral Bis-Oxazoline Ligand 63 81 5.1B: Attempted Chiral Formation of 65 82 5.1C: Synthesis of 65 via Tomioka Method 82 5.2A: Preparation of Noyori’s Ruthenium Catalyst 84 5.2B: Attempted Transfer Hydrogenation of 68 with Noyori’s Catalyst 85 5.3A: Approach to Synthesize DHQZ Enantiomers via Curtius Rearrangement 86 5.4A: Priego’s DHQZ Diastereomer Synthesis 87 5.4B: Approaches Leading to Auxiliary Cleavage and Racemization 87 5.5A: Synthesis of Chiral Auxiliaries 74 and 75 92 XI 5.5B: Effects of Anthranilamide Substitutions on Diastereomer Formation 93 5.5C: Removal of Chiral Auxiliaries 95 5.6A: Synthetic Preparation of the Enantiomers of Compound 61 96 XII List of Abbreviations Biological ADME – adsorption, distribution, metabolism, and elimination ADMET - adsorption, distribution, metabolism, elimination, and toxicity CAM – chicken chorioallantoic membrane assay DNA – deoxyribonucleic acid EDTA – ethylenediaminetetraacetic acid ELISA – enzyme-linked immunosorbent assay FDA – Food and Drug Administration 5FU – 5-fluorouracil GTP – guanine triphosphate HMBE – human bone marrow endothelial cells HMEC – human microvascular endothelial cells HUVEC – human umbilical vein endothelial cells IC50 / GI50 – concentration of drug to inhibit 50% of cell growth IP or ip – intraperitoneal LPS – lipopolysaccharide MTD – maximum tolerated dose MVD – microvessel density NCI – National Cancer Institute PBS – phosphate buffer saline PDGF – platelet derived growth factor XIII Pgp – P-glycoprotein Rr – relative resistance value SAR – structure-activity
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