Design, Synthesis and Screening of Some Anticancer/Antiviral Drug Candidates

416 Pages·2016·10.5 MB·English

University of South Florida
Scholar Commons
Graduate Theses and Dissertations Graduate School
2-7-2016
Design, Synthesis and Screening of
Peptidomimetics for Anticancer and Antiviral Drug
Candidates
Yi Liang
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Liang, Yi, "Design, Synthesis and Screening of Peptidomimetics for Anticancer and Antiviral Drug Candidates" (2016).Graduate
Theses and Dissertations.
http://scholarcommons.usf.edu/etd/6111
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Design, Synthesis and Screening of Peptidomimetics for Anticancer and Antiviral Drug
Candidates

by

Yi Liang

A dissertation submitted in partial fulfillment
of the requirement for the degree of
Doctor of Philosophy
Department of Chemistry
College of Arts and Sciences
University of South Florida

Major Professor: Mark Mclaughlin, Ph.D.
David Morse, Ph.D
Juan Del Valle, Ph.D
Jianfeng Cai, PhD

Date of Approval:
February 2, 2016

Keywords: Peptide, Anti-Myeloma Drug Candidates, Cyclic Peptidomimeticss

Copyright © 2016, Yi Liang
TABLE OF CONTENTS
LIST OF TABLES iii
LIST OF FIGURES iv
LIST OF SCHEMES vi
LIST OF ABBREVIATIONS viii
ABSTRACT xi
CHAPTER ONE INTRODUCTION 1 
1.1 Overview of proteins, peptides and peptidomimetics 1
1.2 Secondary Structure of peptides and proteins 5
1.3 Peptide derivatives in Therapeutics Market 7
1.4 Peptide synthesis 11
1.5 Structural Analysis and Purification of Peptides and Protein 16
1.6 References 25
CHAPTER TWO NOVEL CYCLIC PEPTIDOMIMETICS MTI101 AGAINST
MULTIPLE MYELOMA  37 
2.1 Introduction of Multiple Myeloma 37
2.2 Background of β-hairpin peptides and β turns 39
2.3 Peptide Design 41
2.4 Synthesis of beta-turn promoters and MTI-101 45
2.5 Conclusion 52
2.6 References 53
CHAPTER THREE PEPTIDE AND PEPTIDOMIMETICS IN 3C PROTEASE
DRUG DISCOVERY  57 
3.1 Introduction of Human Rhinovirus (HRV) 57
3.2 Introduction of HRV 3C Protease 59
3.3 Introduction of Coronaviruses 61
3.4 Drug development situation against HRV and CoV 63
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3.5 Structure analysis and design of 3C protease inhibitors 68
3.6 Design and synthesis of warheads 70
3.7 Opimization of P1 73
3.8 Optimization of P2 78
3.9 Optimization of P3 82
3.10 Optimization of P4 84
3.11 The synthesis of unnatural amino acids 88
3.12 Conclusion 91
3.13 References 92
CHAPTER FOUR EXPERIMENTAL PART  98 
CHAPTER FIVE SPECTRUM  203 

ii
LIST OF TABLES
Table 2.1 Turn promoters in cyclic peptidomimetics 42
Table 2.2 SAR studies of cyclic peptide analogs 43

iii
LIST OF FIGURES
Figure 1.1 Primary structure of a protein. 1
Figure 1.2 Structure of peptide. 2
Figure 1.3 Structure (top) and synthesis (bottom) of peptoids. 3
Figure 1.4 Structure of alpha, beta3 and beta2 peptides. 4
Figure 1.5 Composition of all amino acids. 5
Figure 1.6 Structure of alpha helix and beta sheet. 6
Figure 1.7 Red is helix favored amino acids; blue is beta strand favored amino acids 7
Figure 1.8 Global Peptide Therapeutics Market revenue. 9
Figure 1.9 The traditional structure-based design strategies that are used in
peptide drug discovery. 10

Figure 1.10 Solid-phase peptide syntheses on a Rink Amide Resin using 13
Fmoc-α-amine-protected amino acid.
Figure 1.11 Four types of commonly used resins. 14
Figure 1.12 Mechanism of peptide coupling. 15
Figure 1.13 Coupling reagents commonly used in peptide synthesis. 17
Figure 1.14 Rate of Protein Structure Determination by Method and Year. 18
Figure 1.15 The blue arrows represent the orientation of the N – H bond of
selected peptide bonds. 18
Figure 1.16 Far UV CD spectra associated with various types of secondary structure. 20
Figure 1.17 Principles of MALDI 20
Figure 1.18 MALDI-MS used in solid phase peptide/carbohydrate characterization. 22
iv
Figure 1.19 RP-HPLC Separation of three insulins. 23
Figure 1.20 Mechanism of HPLC separation. 23
Figure 2.1 Pathways for cell death in mammalian cells. 39
Figure 2.2 β-hairpin peptides and β-turn. 40
Figure 2.3 Comparison of linear HYD1, cyclized D-cHYD1, and cyclized L-HYD1. 41
Figure 2.4 Structure of MTI-101 45
Figure 3.1 HRV genomic structure. 57
Figure 3.2 Proteases cleaves the protein and how the inhibitors work. 60
Figure 3.3 Cleavage site- AKA PreScission Site- Cleaves Gln and Gly. 60
Figure 3.4 Mechanism of how 3C protease cleaves the petide bond. 61
Figure 3.5 A general coronavirus morphology representative of all coronaviruses. 62
Figure 3.6 SARS 2003 infections report. 63
Figure 3.7 Molecular Modeling of Tripeptidomimetic inhibitors with SARS-Cov binding. 68
Figure 3.8 Molecular modeling of AG7088 (green). 70
Figure 3.9 Designed warheads. 71

v
LIST OF SCHEMES
Scheme 2.1 Synthesis of Fmoc protected methylsulfonamide aminoethyl glycine beta
turn promoter. 46
Scheme 2.2 Synthesis of Fmoc protected prolinol-based promoter. 46
Scheme 2.3 Solid phase synthesis of MTI-101. 47
Scheme 2.4 Synthesis of the N-ethylated beta turn promoter. 49
Scheme 2.5 Synthesis of membrane-seeking beta turn linkers. 50
Scheme 2.6 Synthesis of azide side chain beta turn linkers. 51
Scheme 2.7 Synthesis of prolinol amine derivative promoter. 51
Scheme 2.8 Synthesis of prolinol amine derivative promoter. 52
Scheme 3.1 Synthesis of lactone warhead precursors 72
Scheme 3.2 Synthesis for warhead screening 72
Scheme 3.3 Synthesis of ketoamide warhead 73
Scheme 3.4 General procedure of synthesizing Michael acceptor warhead and the whole
molecule. 73
Scheme 3.5 Synthesis procedures of P1 screening analogs 78
Scheme 3.6 Synthesis of P2-Phe analog 80
Scheme 3.7 Synthesis of other P2 analogs 81
Scheme 3.8 Synthesis of P2 analog with ketoamide warhead 81
Scheme 3.9 Synthesis of P2 skeleton screen 82
Scheme 3.10 Synthesis of P3 screen of P2-Phe analogs 83
vi
Scheme 3.11 Synthesis of P3 screen of P2-Leu analogs 84
Scheme 3.12 Synthesis of P4 screening analogs 88
Scheme 3.13 Synthesis of some unnatural amino acids with cyclohexyl amine side chain 89
Scheme 3.14 Synthesis of some unnatural amino acids 90
Scheme 3.15 Synthesis of some amino acids via Negishi coupling reaction 90
Scheme 3.16 Synthesis of some unnatural amino acids 91

vii
LIST OF ABBREVIATIONS
AA = Amino Acid
ACN = Acetonitrile
Boc = tert-Butoxycarbonyl
BOP = (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
CD = Circular Dichroism
CoV = Coronavirus
DBU = 1,8-Diazabicyclo[5,4,0]undec-7-ene
DCC = N,N’-dicyclohexylcarboiimide
DCM = Dichloromethane
DIC = N,N’-diisopropylcarboiimide
DIEA = N,N-diisopropylethylamine
DMF = N,N-Dimethyl Formamide
DMPK = Drug Metabolism and Pharmacokinetics
DMSO = Dimethylsulfoxide
DNA = Deoxyribonucleic acid
EA = Ethyl acetate
EDC = 1-Ethyl-3-[3-(dimethylamino)propyl]carboiimide
EDT = Ethanedithiol
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