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Proquest Dissertations Design and synthesis of topographically constrained amino acids, and bioactive peptides for studies of ligand- receptor interaction, and for de novo design of delta-opioid selective non-peptide mimetics as potential therapeutics Item Type text; Dissertation-Reproduction (electronic) Authors Liao, Subo, 1963- Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 11/10/2021 09:20:23 Link to Item http://hdl.handle.net/10150/282418 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 frwe, while others may be fi-om 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 photogn^hs, print bleedthrough, substandard margins, and improper alignment can adverse^ affect reproductioiL 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 indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, b^inning at the upper left-hand comer and continuing from left to right in equal sections with small overiaps. 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. UMI A Bell & Howdl Difoiniaiion Compai^ 300 North Zeeb Road, Ann Aibor MI 48106-1346 USA 313/761-4700 800/521-0600 DESIGN AND SYNTHESIS OF TOPOGRAPHICALLY CONSTRAINED AMINO ACIDS, AND BIOACTIVE PEPTIDES FOR STUDIES OF LIGAND-RECEPTOR INTERACTION, AND FOR DE NOVO DESIGN OF 5-OPIOID SELECTIVE NON-PEPTIDE MIMETICS AS POTENTL\L THERAPEUTICS By Subo Liao Copyright © Subo Liao 1997 A Dissertation Submitted to the Faculty of the Department of Chemistry In Partial Fulfillment of the Requirements For Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 1997 DMX Number: 9806802 Copyright 1997 by Liao, Subo All rights reserved. UMI Microronn 9806802 Copyright 1997, by UMI 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 2 THE UNIVERSITY OF ARIZONA. « GRADUATE COLLEGE As members of the Final Examination Committee, we certify that we have read the dissertation prepared by Subo Liao entitled Design and Synthesis of Topographically Constrained Amino Adds. and Bioactive Peptides for Studies of Ligand-Receptor Interaction, and For De Novo Design of delta-Opioid Selective Non-Peptide Mimetics as Potential Therapeutics and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy Date U~7 Date Richard Glass Eugene A. Mash, Jr. Date r'/W/>z rj I. Y4;nii«iura Date ' David E. Wi Date ( ' Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. Dissertation Date 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfiUlment of requirements for an advanced degree at The University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations &om this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the copyright holder. SIGNED: 4 ACKNOWLEDGMENT First of all, I would like to give my warmest thanks to my research advisor Prof. Victor J. Hruby. Elis wisdom, experience, understanding, patience and ready-to-go help always make me feel I am so lucl^ to work with him. He not only lead me to an exciting scientific field, helped me open my mind, taught me the way to think, and offered me the opportunity to develop my independent research capability, but also is my model as a decent human being and excellent scientist whose impact on me in the past five years will influence me throughout my lifetime. I would also give my special thanks to all my committee members: Profs. Richard S. Glass, Robin L. Polt, Henry I. Yamamura, Gene Mash, David Wigley and William R. Salzman for their rime and their very helpful discussion about research-related and other issues. I would like to thank Profs. Jacquelyn Gervay, Walter N^er, Michael Burke, Dermis Lichtenburger, and John Round who were my course instructors. I also would like to express my appreciation to Profs. Frank Porreca and Jirina Slaninova for their generous help and discussion about peptide bioassays, and pharmocologests Keiko Hosohata, Dagmar Stropova and Peg Davis for performing the bioassays, and Dr.Hruby's administrative assistants Cheryl McKinley and Margie Colie for their generous help in various matters. I would also like to take this opportunity to thank the postdoctoral and visiting professors who worked in Prof. Hmby's laboratory in the past several years for their help and discussion in the development of my chemistry knowledge, experimental skill and my scientific thinking. The collaborations and friendships with them are one of the most wonderful memories I will keep in my heart forever. Among them are Drs. Mark D. Shenderovich, Yinglin Han, Zhigang Zhang, Jun Lin, Katalin E. Kover, Bob Ouyang, Bi- Show Lou, Li Xiang, Wei Yuan, and Aleksandra Misicka. There are many graduate smdents who deserve my appreciation in this department, in particular, I would also give my special thanks for graduate students I share fiiendships with including Drs. Xinhua Qian, Guigen Li, Yangqi Liu, Tiffini Lung, and my peer graduate students; Josue Alfaro-Lopez, Huiwei Wu, Wei Qiu, and Chaozhong Cai. I would also like to thank the Department of Chemistry at the University of Arizona for my teaching assistantship, Mid-Career Awards(1993-1994, 1994-1995) and Carl S. Marvel fellowship(finalist, 1996), and NIDA and NTH for my research assistantships. The Victor J. Hruby Alumni Foundation for Victor J. Hruby Fellowship in Peptide Research (1995), the UA Graduate College for The Dean's Fellowship (1996-1997), and American Peptide Society for Travel Award (1997, 15th APS Symposium). 5 DEDICATION I would like to dedicate this work to my wtfe Xiaohong Xiao, and my parents, Fangyong Liao and Fengyin Lian, and my parents-in-law, Yin Xiao and Xiujuan Yang, my sister Jingbo Liao and my bother Xunbo Liao. 6 TABLE OF CONTENTS I. UST OF ILLUSTRATIONS 9 n. LIST OF TABLES 13 m. ABSTRACT 16 IV. CHAPTER 1. INTRODUCTION: PEPTIDES AND PEPTIDE- BASED DRUGS 18 V. CHAPTER 2. DESIGN CONFORMATIONALLY CONSTRAINED BIO ACTIVE PEPTIDES 24 2.1. Introduction 24 2.2. Peptide conformation 28 2.3. Local backbone constraints 30 2.4. Global backbone constraints 34 2.5. Secondary structure templates 38 2.6. Topographically constraints 40 VI. CHAPTER 3. DESIGN AND SYNTHESIS OF TOPOGRAPHICALLY CONSTRAINED DESIGNER AMINO ACIDS 44 3.1. Introduction 44 3.2. Design and retrosynthetic analysis 46 3.3. Synthesis and discussion 48 3.4. Computer-assisted conformational studies 57 3.5. Experimental 63 Vn. CHAPTER 4. DESIGN, SYNTHESIS AND DYNAMICS OF 2,3- METHANO AROMATIC AMINO ACIDS 77 4.1. Introduction 77 7 TABLE OF CONTENTS-Continued 4.2. Design and retrosjmthedc analysis 80 4.3. Synthesis and discussion 83 4.4. Confonnational and dynamic studies 88 4.5. Experimental 94 Vm. CHAPTER 5. DESIGN TOPCXJRAPHICALLY CONSTRAINED S-OPIOID SELECTIVE BIO ACTIVE PEPTIDES 105 5.1. Introduction 105 5.2. Design, synthesis and biological evaluation of [p-iPrPhe']-DELT 1 115 5.3. Conformational studies of [P- iPrPhe']DELT 1 122 5.4. Design, synthesis and biological evaluation of TMT-Tic 134 5.5 Conformational studies of TMT-Tic 137 5.6. Experimental 139 IX. CHAPTER 6. DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION OF TOPOGRAPHICALLY CONSTRAINED BICYCLIC OXYTOCIN ANTAGONISTS 150 6.1. Introduction 150 6.2. Desi^, synthesis and conformation-activity relationship 156 6.3. Experimental 165 X. CHAPTER 7. DESIGN AND SYNTHESIS OF 5-OPIOID SELECTIVE NON-PEPTIDE MIMETIC AGONISTS BASED ON PEPTIDE LEADS 172 7.1. Introduction 172 7.2. Design, synthesis and structure-activity relationship 175 8 TABLE OF CONTENTS-Continued 7.3. Experimental 187 XI. CHAPTER 8. FUTURE PLAN 197 Xn. REFERENCES 203 9 LIST OF ILLUSTRATION Figure 1.1, Definition of an L amino acid, and the amino acid residue in polypeptide chain 18 Figure 1.2, A model of peptide-receptor interaction in solution 20 Figure 2.1, An outline of the interactions between biophysical methods, chemical methods, structural-activity relationship, conformational considerations,
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