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Information to Users INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. U M I 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. The 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 U M I 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 corner 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 U M I directly to order. University Microfilms international A Bell & Howell Information Company 300 North Zeeb Road. Ann Arbor. Ml 48106-1346 USA 313-761-4700 000.521-0600 Order Number 9412014 Arachidonic acida ct-reductone strategies: Asymmetric syntheses of 2-hydroxy tetronic acid antimetabolites Mantri, Padmaja, Ph.D. The Ohio State University, 1993 UMI 300 N. Zeeb Rd. Ann Arbor. M l 48106 ARACHIDONIC ACID ac/-REDUCTONE STRATEGIES: ASYMMETRIC SYNTHESES OF 2-HYDROXYTETRONIC ACID ANTIMETABOLITES DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of the Ohio State University By Padmaja Mantri, B.S. The Ohio State University 1993 Dissertation Committee: Approved by Dr. Donald T. Witiak Dr. Robert W. Brueggemeier Dr. Dennis R. Feller Advisor Dr. Michael H. Zehfus College of Pharmacy To Ayn Rand ii ACKNOWLEDGEMENTS To the following, I express my gratitude and appreciation for their help and support. Professor and Dean Donald T. Witiak, my advisor for his guidance, enthusiasm, advice, persistence, patience, and never ending support. Neelam Gupta for the initial financial support that made graduate studies possible. Prabhakar and Shabana for intellectually stimulating discussions about chemistry and philosophy and for their much valued friendship. Dr. Dennis R. Feller and Dr. Karl J. Romstedt for providing the associated pharmacological support. Dr. Cottrell, Dr. David Chang and Dr. Kurt Loening for their help in procurring NMR, mass spectral data and chemical nomenclature, respectively. The faculty, staff, my dissertation committee and colleagues, Pat and Al for help and suggestions. My parents, Madhukar Mantri and Vijaya Mantri for their love, support and patience. Pineabrim McCullough Jr., whose love, understanding and encouragement made this time period enjoyable. The Ohio State University, University of Wisconsin-Madison and American Cancer Society (Ohio Division) for financial support. VITA August 20, 1967 ........................................... Bom- Bombay, India 1989................................................................ B.S. Pharmacy, C.U.Shah College of Pharmacy, S.N.D.T. University, Bombay, India 1989-199 0.................................................... Graduate Fellow, The Ohio State University, Columbus, Ohio 1990-199 2.................................................... Graduate Teaching Assistant, The Ohio State University, Columbus, Ohio 1992-1993.................................................... Graduate Research Associate, The Ohio State University, Columbus, Ohio 1989-1993.................................................... Academic Challenge Fellow, The Ohio State University, Columbus, Ohio PRESENTATIONS Mantri, P.M. and Witiak, D.T. Approaches to the asymmetric syntheses of polyalkenyl-2-hydroxytetronic acids: Potential promoters of IL-2-induced lymphokine activated killer activity. American Cancer Society International symposium, September 9-12,1992, Columbus, OH. Mantri, P.M. and Witiak, D.T. ac/-Reductone chemistry and biology: Asymmetric syntheses for 4-substituted-2-hydroxytetronic acids. 205th ACS National Meeting, March 28-April 2,1993, Denver, CO. iv Witiak, D.T., Triozzi, P.L., Feller, D.R., Romstedt, K.J., Tehim, A.K., Hopper, A.T. and Mantri, P.M. 4-Substituted-2-hydroxytetronic acid aci- reduct ones improve lymphokine-activated killer cell activity in vitro. 84th Annual Meeting of the American Association for Cancer Research, May 19-22,1993, Orlando, FL. FIELD OF STUDY Major Field: Pharmacy Studies in : Medicinal Chemistry v TABLE OF CONTENTS DEDICATION....................................................................................................... ii ACKNOWLEDGEMENTS...................................................................................iii VITA..................................................................................................................... iv LIST OF TABLES..............................................................................................viii LIST OF FIGURES..............................................................................................ix CHAPTER Page I INTRODUCTION AND HISTORICAL BACKGROUND 1 Prostaglandin H synthase ................................................ 1 Inflammation ..................................................................... 8 Cyclooxygenase inhibitors ...............................................9 Stereochemical preferences of cyclooxygenase ................................................... 20 Metabolism of asymmetric propionic acids ...............23 5-Lipoxygenase............................................................... 27 Substrate and product analogues ...............................33 FLAP inhibitors................................................................37 Iron chelators ...................................................................45 Antioxidants, which scavenge free radicals ..............60 Stereochemical preferences of 5-lipoxygenase .................................................... 62 II aci-REDUCTONES.....................................................................64 Introduction ......................................................................64 Drug Design....................................................................66 Biological properties.......................................................67 Synthetic chemistry ........................................................ 69 vi III STATEMENT OF THE PROBLEM............................................75 IV RESULTS AND DISCUSSION.................................................81 Method A Unsuccessful Organocuprous condensation approach .....................................83 Method B Successful Wittig reaction approach ............................................................. 94 V EXPERIMENTAL SECTION....................................................116 BIBLIOGRAPHY...................................................................... 158 vii LIST OF TABLES TABLE PAGE 1. Classification of nonsteroidal antiinflammatory drugs ......................... 9 2. Inhibitory constants of NSAIDs derived hydroxamates .....................47 3. Comparison of in vitro and in vivo inhibitory constants of type A and type B hydroxamate .....................................53 4. Comparison of inhibitory constants and pharmacokinetic parameters of type A, type B hydroxamates and N-hydroxyureas .............................................................................. 59 LIST OF FIGURES FIGURE PAGE 1. Interaction of 5-lipoxygenase and 5-lipoxygenase activating protein .....................................................................................30 2. 5-Lipoxygenase inactivation by antioxidants .......................................61 CHAPTER I INTRODUCTION AND HISTORICAL BACKGROUND All mammalian cells, except red blood cells, produce potent inflammatory mediators; among these are the prostaglandins (PG), prostacyclins, thromboxanes (TX) and leukotrienes (LT). Physiologically, these autacoids produce inflammation, pain and fever, regulate blood pressure and induce blood clotting. However, abnormal eicosanoid concentrations are observed in pathological conditions such as rheumatoid arthritis, psoriasis, asthma, anaphylactic shock and ulcerative colitis. This has provided the impetus for developing inhibitors of autacoid biosynthetic enzymes, PGH synthase and 5-lipoxygenase (5-LO). Prostaglandin H Synthase: Prostaglandin H synthase (PGH synthase) catalyzes the committed step in the biochemical synthesis of autocoids, PGs, prostacyclins and TXs. PG biosynthesis utilizes the substrate arachidonic acid (AA, 1), present as a triglyceride ester in the cell membranes. The rate-limiting step in AA metabolism involves hydrolysis of triglycerides or phospholipids by phospholipases to generate free eicosanoid AA. PGH synthase is ubiquitous in all cell types; however, the generation of various PGs, prostacyclins and TXs is tissue- specific. This specificity resides in the selective presence of enzymes that convert PGH 2 to different autacoids. For example, only TXs are 1 2 generated in blood platelets, whereas
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