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Information to Users INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. H ie quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. A Bell & Howell information Company 300 North Zeeb Road. Ann Arbor. Ml 48106-1346 USA 313/761-4700 800/521-0600 Synthesis, Evaluation and Mechanistic Studies of Halogenated Psoralen and Acridine Photosensitizers A Dissertation Presented in Partial Fufillment of Requirements for the Degree of Doctor of Philosophy in the Graduate School of the Ohio State University By Tongqian Chen * * * i|i 4c The Ohio State University 1995 Dissertation Committee: Approved by Dr. Matthew S. Platz Dr. James A. Cowan Dr. Gideon A. Fraenkel UMI Number: 9526010 UMI Microform 9526010 Copyright 1995, by DMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 To my beloved parents, Yicheng and Caimei, whose life-long suffering has paved my way. To my beautiful wife, Lingxia, who has suffered bravely and selflessly. and To my lovely dauther, Shannon, who reminds me that life is not suffering only. ACKNOWLEDGMENTS I wish to express my sincere gratitude to Dr. Matthew Platz for being an excellent academic advisor as well as a life mentor. Many thanks are extended to the past and present members of Platz’s research group who are too numerous to mention individually for their coorperation, help and friendship. Of particular help, Dr. Sang-Chul Park provided me with certain sensitizers of his own creation wich were used in this project. I also thank him for his great frendship and encouragement. I am grateful to Dr. Chanderica Kasturi who imparted to me many biotechniques. I appreciate Dr. Jacek Michalak who cooperated with me in the studies of azido psoralens and taught me the laser flash photolysis technique. I also enjoy Dr. John Toscano’s help in using laser flash photolysis instruments and being a great consultant. I also acknowledge Cryopharm Corporation for financial support. Above all, I am deeply in debt to my wife, Lingxia, who gave up her comfortable life at home and came with me abroad. During my whole graduate study here, her constant care and support was invaluble. Without her, everything would be impossible. VITA Sept. 19, 1964 ....................................................... Bom - Yuhuang, Zhejiang, China. 1986 ........................................................................B. S. Ocean University of Qingdao Qingdao, Shandong, China 1986-1989 ............................................................. Graduate Research Associate Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences Shanghai, China 1989 ........................................................................M.S. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences Shanghai, China 1990-1992 ............................................................. Graduate Teaching Associate The Ohio State University Columbus, OH 1993-1994 ............................................................. Graduate Research Associate The Ohio State University Columbus, OH iv PUBLICATIONS Biqi Wu, Tongqian Chen. Guojian Ou, and Lixin Dai. “A New Method to Synthesis of Acetylenic Amides”, Youji Huaxue(Chinese J. Org. Chem.) 1989,9,431. Matthew S. Platz, Tongqian Chen, et al. “The Design and Development of Selective Viral Inactivation Sensitizers For Sterilization of Blood Products” , In “Prevention of Transfusion Mediated Diseases” . Fritz Sieber Ed. CRC Press, in press. Tongqian Chen. Jacek Michalak, and Matthew S. Platz. “Exploratory Photochemistry of 5-Azido*8-Alkoxy Substituted Psoralens Free and Bound toDNA”. Submitted to Photochemistry & Photobiology. Tongqian Chen. Eric Voelk, and Matthew S. Platz “Dramatic Improvements in Viral Inactivation with a Halogenated Intercalator 2. 3-Amino-6-iodoacridine”. Submitted to Photochemistry & Photobiology. FIELD O F STUDY Major Field: Chemistry v TABLE OF CONTENTS DEDICATION................................................................................................................... ii ACKNOWLEDGEMENTS............................................................................................. iii VITA.................................................................................................................................... iv LIST OF FIGURES........................................................................................................... ix LIST OF SCHEMES......................................................................................................... xi LIST OF TABLES............................................................................................................ xiii LIST OF PLATES............................................................................................................. xiv LIST OF SPECTRA.......................................................................................................... xv ABBREVIATIONS........................................................................................................... xix CHAPTER I. INTRODUCTION.................................................................................... 1 1.1 Problem Definition .......................................................................................... 1 1.2 Drug Design Strategies .................................................................................. 2 1.3 Scope and Objective ....................................................................................... 4 CHAPTER II. LITERATURE OVERVIEW................................................................ 6 II. 1 Drug-DNA Interaction ............................................................................... 6 II. 1.1 Formation of Covalent Bonds between Small Molecules and DNA............................................................................................... 7 II. 1.2 Groove Binding via Non-Covalent Bond Forces ................... 15 II. 1.3 Interaction by Planar Aromatic Molecules between Base Pairs of DNA ................................................................................ 26 II.2 Photoinduced Electron Transfer Reactions Relative to DNA.............. 30 11.2.1 Theoretical Aspects of Electron Transfer Reactions ............... 31 11.2.2 Radical Reactions of DNA Bases ............................................... 41 vi II.2.3 Reagents for DNA Cleavage ...................................................... 50 II.3 Overview of Psoralens ................................................................................. 52 CHAPTER III. RESULTS AND DISCUSSION......................................................... 62 III. 1 Sythesis .......................................................................................................... 63 111.2 Solubilities in Aqueous Media .................................................................. 71 111.3 Binding Constants with DNA .................................................................... 71 111.4 Photophysics of Sensitizers ........................................................................ 78 111.5 Photochemistry of Sensitizers ................................................................... 89 III.5.1 Photochemistry of Acridines ..................................................... 89 111.5.2 Photochemistry of Halogenated Psoralen Derivatives 92 111.5.3 Photochemistry of Azido Psoralens ......................................... 95 111.6 Sensitized Unwinding and Cleavage of Plasmid DNA ........................ 98 111.6.1 DNA Photocleavage with Acridines ........................................ 99 111.6.2 DNA Photocleavage with Psoralen Derivatives ..................... 100 111.7 Linght Induced Viral Inactivation ............................................................. 105 111.8 Possible Reaction Mechanisms of Sensitizers with DNA ..................... 115 111.9 Conclusion .................................................................................................... 120 CHAPTER IV. EXPERIMENTAL................................................................................ 123 IV. 1 Materials................. 123 IV.2 General Procedure ....................................................................................... 124 IV.3
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