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Structure–Activity Relationship Studies of Hybrid Antitumor STRUCTURE–ACTIVITY RELATIONSHIP STUDIES OF HYBRID ANTITUMOR AGENTS FOR THE TREATMENT OF NON-SMALL CELL LUNG CANCER BY ZHIDONG MA A Dissertation Submitted to the Graduate Faculty of WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Chemistry December 2009 Winston–Salem, North Carolina Approved By: Ulrich Bierbach, Ph.D., Advisor _____________________________ Examining Committee: James P. Vaughn, Ph.D. (Chair) _____________________________ Rebecca Alexander, Ph.D. _____________________________ Christa L. Colyer, Ph.D. _____________________________ S. Bruce King, Ph.D. _____________________________ ACKNOWLEDGEMENTS The pursuit of a Ph.D. degree is a challenging journey, filled with success, failure, friendship, loneliness, happiness, and frustration. It took me five years of my Ph.D. to understand the significance of this degree. Reading journals, discussing with colleagues and thinking independently in the field of chemistry and biomedical research helped me understand medicinal chemistry and its great contributions to health care and society. Therefore, I really want to thank my dissertation advisor, Professor Ulrich Bierbach, not only for teaching me the detailed technical skills everyday in the past five years, but also leading me to explore a new world of medicinal chemistry. Every time I had a question, he is always there to help me out. I really appreciate his “tough love” as my advisor helping me build my scientific career and his “soft love” as my friend helping me through my Ph.D. years. I would also like to acknowledge my committee members, Professor James Vaughn, Professor Rebecca Alexander, Professor Christa Colyer, and Professor Bruce King, for reading my dissertation and giving me constructive suggestions during my Ph.D. study. I would also like to thank Dr. Cynthia Day for her great help with crystallography, and Dr. Marcus Wright for his patient in teaching me NMR spectroscopy. Our collaborators helped me new techniques and allowed me to perform my experiments in their labs. I want to show my appreciation to our collaborators Dr. Bradley Jones, Carl Young and Dr. Keith Levine at Research Triangle Institute for allowing me to perform the ICP-MS experiment, Dr. Gregory L. Kucera and Gilda Saluta at Wake Forest University Baptist Medical School for teaching me how to perform cytotoxicity assays, and Dr. Trevor Hambley, Dr Nicole Bryce, and Alice Klein at The I University of Sydney for the opportunity to perform confocal fluorescence microscopy studies in their lab. My past and present lab members are really precious to me. We have shared so much memorable time together. Thank you Dr. Rajsekhar Guddneppanavar, Dr. Jayati Roy Choudhury, Lauren Eiter, Lu Rao, Leigh Ann Graham, Amanda Pickard, Partha Choudhury, Gary Wilson, Chandra Vemulapalli, Tony DeMartino, Bart Steen, Josh Dworkin, Jennifer Nguyen. Without your company, it would have been painful to be alone in the lab. My friends also play a very important role during my time in Wake Forest. We always had a lot of fun together. I would like to thank my friends and chemist fellows Michael Budiman, Subhasis De, Jiyan, Maben, Liqiong, Xiuli, Lei, Ranjan, Saurva, Salwa, Erika and Veronica. The funding was also important to me, without which it would have been impossible for me to continue my research. I would like to thank the Richter Scholar Award, the National Cancer Institute (Grant RO1 CA101880) and Wake Forest University for supporting my Ph.D. work. II This dissertation is dedicated to my beloved grandma, father, mother and brother. III TABLE OF CONTENTS Page List of Tables VIII List of Figures X List of Abbreviation XVII Abstract XXI Chapter 1 Introduction 1 1.1 Cancer: Lung Cancer 1 1.1.1 Cancer Statistics 1 1.1.2 Non-Small-Cell Lung Cancer 1 1.2 Chemotherapy of Lung Cancer 2 1.2.1 DNA-targeted Cytotoxic Agents 3 1.2.2 Targeted Therapies 17 1.3 Platinum Antitumor Agents 18 1.3.1 Bifunctional Platinum Crosslinkers 18 1.3.2 Monofunctional Platinum Complexes 24 1.3.3 Other Non-classical Platinum Agents 25 1.3.4 Platinum–Intercalator Conjugates 28 1.4 Background and Significance of the Doctoral Research Program 30 1.4.1 The Development of PT-ACRAMTU 30 1.4.2 Synthesis of PT-ACRAMTU 32 1.4.3 Biological Activity and DNA Binding Mechanism 33 1.4.4 Goals of the Doctoral Research Program 35 IV Chapter 2 Synthesis, Characterization, and Biological Evaluation of Guanidine Derivatives of ACRAMTU 2.1 Background 39 2.2 Experimental Section 43 2.2.1 Materials and Chemicals 43 2.2.2 Syntheses and Characterizations of Guanidine Derivatives 43 2.2.3 Crystallization and Data Collection 48 2.2.4 Biological Characterization: pKa Determinations, DNA Binding Affinities and Cell Proliferation Assay 48 2.3 Results and Discussion 50 2.3.1 Two Unusual Reactivity Features of the 9-Aminoacridine Chromophore 50 2.3.2 Biological Evaluation: pKa Determinations, DNA Binding Constants, and Cytotoxicities 57 2.3.3 Attempted Conjugation of ACRAMGU (38) with Monofunctional Platinum 60 2.4 Conclusions 61 Chapter 3 Synthesis, Characterization, and Biological Evaluation of Amidine Derivatives of PT-ACRAMTU 3.1 Background 63 3.2 Experimental Section 64 3.2.1 Materials and Chemicals 64 V 3.2.2 Synthesis and Characterization 65 3.2.3 Cell Proliferation Assay 69 3.2.4 Crystallization and Data Collection 70 3.2.5 NMR Spectroscopy 70 3.2.6 Liquid Chromatographic Separation–Mass Spectrometry Detection 71 3.2.7 Confocal Fluorescence Microscopy 72 3.2.8 H460 Xenograft Study 73 3.2.9 Inductively Coupled Plasma–Mass Spectrometry Detection of Platinum 74 3.3 Results and Discussion 75 3.3.1 Lewis Acid Assisted Addition Reaction 75 3.3.2 Design Rationale 77 3.3.3 Biological Activity 79 3.3.4 Kinetics of Platinum Binding with Biologically Relevant Nucleophiles 81 3.3.5 Analysis of Platinum–Amino Acid Products 92 3.3.6 Determination of the Subcellular Localization of Complex 54 99 3.3.7 Antitumor Activity and Systemic Toxicity 106 3.3.8 Distribution of Platinum in Murine Tissue Samples 108 3.4 Conclusions and Clinical Implications 112 VI Chapter 4 Changing the Connection Site of the Linker in PT-ACRAMTU from the 9-Position to the 4-Position 4.1 Background 116 4.2 Experimental Section 117 4.2.1 Materials and Methods 117 4.2.2 Synthesis and Characterization 118 4.2.3 Biological Characterization: pKa Determinations and Cell Proliferation Assay 121 4.3 Results and Discussion 123 4.3.1 Synthesis of Acridine-4-Carboxamides 123 4.3.2 Acid–Base Chemistry 124 4.3.3 Cytotoxicities 125 4.4 Conclusions 126 Chapter 5 Summary and Outlook 129 References 132 Appendix A 155 Appendix B 172 Appendix C 189 Scholastic Vita 191 VII LIST OF TABLES Page Table 1. Cytotoxicity of PT-ACRAMTU (31) in NSCLC. 33 Table 2. Summary of Chemical and Biological Characterization for 38, 40 and 43. 58 Table 3. Cytotoxicity Data (IC50, μM) for Platinum–Acridine Conjugates. 80 Table 4. Platinum Concentrations in Various Biological Tissues (Tumors, Kidneys and Lungs) at Two Different Doses (0.1 mg/kg and 0.5 mg/kg) Determined by ICP–MS after 16 Hours of Tissue Digestion. 111 Table 5. Retention of Platinum Per Single Organ Calculated as a Percentage of the Total Administered Doses (0.1 mg/kg and 0.5 mg/kg) Determined by ICP–MS after 16 Hours of Tissue Digestion. 112 Table 6. Acid–Base Properties and In Vitro Cytotoxicity (IC50, μM) of Acridines and Platinum Acridines in HL-60 and NCI-H460 Cell Lines. 125 Table B1. Summary of X-ray Crystallographic Data for 1-[2-(Acridine-9- ylamino)- ethyl]-1,3-dimethylguanidine Dihydrochloride (ACRAMGU·2HCl), 38. 172 Table B2. Bond Lengths [Å] and Angles [°] for 1-[2-(Acridine-9- ylamino)-ethyl]-1,3-dimethylguanidine Dihydrochloride (ACRAMGU·2HCl), 38. 173-175 VIII Table B3. Summary of X-ray Crystallographic Data for (Z)-N- [1-(Acridin-9-yl)-3-methylimidazolidin-2-ylidene]methanaminium Hydrochloride, 40. 176 Table B4. Bond Lengths [Å] and Angles [°] for (Z)-N- [1-(Acridin-9-yl)-3-methylimidazolidin-2-ylidene]methanaminium Hydrochloride, 40. 177 Table B5. Summary of X-ray Crystallographic Data for 2′- (1H-Imidazol-1-yl)-8′-methyl-7′,8′-dihydro-6′H,10H-spiro- [acridine-9,4′-imidazo[1,2-a][1,3,5]triazine], 42. 178 Table B6. Bond Lengths [Å] and Angles [°] for 2′-(1H-Imidazol- 1-yl)-8′-methyl-7′,8′-dihydro-6′H,10H-spiro-[acridine- 9,4′-imidazo[1,2-a][1,3,5]triazine], 42. 179-180 Table B7. Summary of X-ray Crystallographic Data for 1-(Acridin- 9-yl)-3-methyl- imidazolidin-2-imine Hydrobromide, 43. 181 Table B8. Bond Lengths [Å] and Angles [°] for 1-(Acridin- 9-yl)-3-methyl-imidazolidin-2-imine Hydrobromide, 43. 182 Table B9. Summary of X-ray Crystallographic Data for [Pt(EtCN)(C19H22N4)Cl2], 50. 183 Table B10. Bond Lengths [Å] and Angles [°] for [Pt(EtCN)(C19H22N4)Cl2], 50. 184-185 Table B11. Summary of X-ray Crystallographic Data for [PtCl(en)(C19H23N4)](NO3)2, 54. 186 Table B12. Bond Lengths [Å] and Angles [°] for IX [PtCl(en)(C19H23N4)](NO3)2, 54. 187-188 Table C1. Platinum Concentrations in Various Biological Tissues (Tumors, Kidneys and Lungs) at Two Different Doses (0.1 mg/kg and 0.5 mg/kg) Determined by ICP–MS After 16 Hours of Digestion. 189 Table C2. Masses of Various Biological Tissues (Tumors, Kidneys and Lungs). 190 LIST OF FIGURES Page Figure 1. Timeline: The history of chemotherapy. 3 Figure 2. Watson–Crick base pairs (GC and AT) with the major and minor grooves highlighted.
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