Synthesis and Biological Evaluation of Antibiotics Targeting the Ribosome

270 Pages·2014·4.83 MB·English

UC San Diego
UC San Diego Electronic Theses and Dissertations
Title
Synthesis and Biological Evaluation of Antibiotics Targeting the Ribosome
Permalink
https://escholarship.org/uc/item/3c44470d
Author
Fair, Richard James
Publication Date
2014

Peer reviewed|Thesis/dissertation
eScholarship.org Powered by the California Digital Library
University of California
UNIVERSITY OF CALIFORNIA, SAN DIEGO

Synthesis and Biological Evaluation of Antibiotics Targeting the Ribosome

A dissertation submitted in partial satisfaction of the requirements for the degree Doctor
of Philosophy

in

Chemistry

by

Richard James Fair

Committee in Charge:
Professor Yitzhak Tor, Chair
Professor Jeffery Esko
Professor Kamil Godula
Professor Thomas Hermann
Professor Ulrich Muller

2014
Copyright
Richard James Fair, 2014
All rights reserved.
The dissertation of Richard James Fair is approved, and it is acceptable in quality and
form for publication on microfilm and electronically:

Chair

University of California, San Diego
2014

iii
DEDICATION

For my parents, Patricia and Rick Fair, and my sister, Megan Fair.

iv
TABLE OF CONTENTS
Signature Page………………………………………………………………….……...…iii
Dedication……………………………………………………………………….………..iv
Table of Contents………………………………………………………………….………v
List of Figures……………………………………………………………………………vii
List of Schemes…………………………………………………………………………..ix
List of Tables………………………………………………………………….……...…..xi
Abbreviations…………………………………………………………………………….xii
Acknowledgements………………………………………………………………………xv
Vita……………………………………………………………………………....……..xvii
Abstract of the Dissertation……………………..……….………………………….....xviii
Chapter 1: Bacterial Resistance and Antibiotic Development…………………………….1
1.1 The Rise of Antibiotic Resistance……..………………………………………1
1.2 Emergent Bacterial Threats………………………………..……....…………..8
1.3 A Brief History of Established Antibiotic Classes…………….....………….21
1.4 The Search for New Antibiotic Classes in the 21st Century….……..……….53
1.5 References………………………….………………………………………...69
Chapter 2: Selectively Guanidinylated Aminoglycosides as Antibiotics………………..89
2.1 Introduction……………………………………..……………………………89
2.2 Results………………………..………………………………………………92
2.3 Discussion…………..………………………………………………………102
2.4 Conclusions……………………………………..………………………..…105
2.5 Experimental………..……………………………………………………....105
2.6 References………………..…………………………………………...…….146
Chapter 3: RNA Binding and Antibacterial Activity of Guanidinoglycosides…………149
3.1 Introduction………..………………………………………………………..149
3.2 Results and Discussion……………………..…………………………...….151
3.3 Conclusions………………………….……………………….………….….155
3.4 Experimental………………….……...……………………………………..155
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3.5 References…………………………..………………………………………165
Chapter 4: Singly Modified Amikacin and Tobramycin Derivatives Show Increased A-
Site Binding and Higher Potency against Resistant Bacteria…………………………..167
4.1 Introduction………………………………..….…………………………….167
4.2 Results……………………………...……………………………………….169
4.3 Discussion…………………………..………………………………………180
4.4 Conclusions………………………..………………………………………..182
4.5 Experimental……………..…………………………………………………183
4.6 References……………………………..……………………………………208
Chapter 5: Synthesis and Biological Evaluation of Aromatic TAN-1057 Analogs…....211
5.1 Introduction………………………..…………………………………….….211
5.2 Results and Disucssion………..……………………………………………215
5.3 Conclusions…………………………………..………….………………….225
5.4 Experimental…………………………..……………………………………226
5.5 References………………………..…………………………………………239
Chapter 6: A Safe and Cost-Effective Synthesis of 3-Lysine…………………...…….241
6.1 Introduction………………………………………..…….………………….241
6.2 Results and Discussion…………………..…………………………………245
6.3 Conclusions……………………...………………………………………….247
6.4 Experimental…………………………...……………………..…………….247
6.5 References……………………………...…………………………………...249

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LIST OF FIGURES
Figure 1.1: Sulfonamides…………………………………………………….…………..23
Figure 1.2: -lactams…………………………………………………………………….24
Figure 1.3: Aminoglycosides…………………………………………………………….29
Figure 1.4: Cloramphenicol………………………………………………...……………32
Figure 1.5: Macrolides and the ketolide, telithromycin………………………………….33
Figure 1.6: Tetracyclines and the glycylcycline, tigecycline...…………………………..35
Figure 1.7: Rifampicin……………………...……………………………………………37
Figure 1.8: Glycopeptides……………………………...…………………………...........39
Figure 1.9: Quinolones…………………………………………………………………...41
Figure 1.10: Streptogramins………………………...……………………………………43
Figure 1.11: Polymyxins………………………………...……………………………….45
Figure 1.12: Oxazolidinones…………………...………………………………………...47
Figure 1.13: Daptomycin……………………………...…………………………………49
Figure 1.14: Retapmulin……………...……………………………………………….....50
Figure 1.15: Fidaxomicin……………...…………………………………………………51
Figure 1.16: Bedaquiline………………………...……………………………………….52
Figure 1.17: Antibiotic class clinical introduction timeline……………..………………53
Figure 1.18: Totally synthetic potential antibiotics……...………………………………58
Figure 1.19: Natural product potential antibiotics…………………………...…………..62
Figure 1.20: Potential combination therapies…………………………...……………….65
Figure 2.1: Parent aminoglycosides and guanidino-aminoglycosides……..………….…92
Figure 2.2: Representative A-site displacement curve…………………………..………98
Figure 2.3: Proposed interactions between guanidinium groups and A-site bases……..103
Figure 2.4: Tobramycin COSY………………………………..……………...………...129
Figure 2.5: Tobramycin COSY expanded………………………..……………...……..130
Figure 2.6: 6’-Guanidinotobramycin COSY………………..…………...……………..131
Figure 2.7: 6’-Guanidinotobramycin COSY expanded………………...………..……..132
Figure 2.8: Amikacin COSY………………………………..……………...…………..134
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Figure 2.9: Amikacin COSY expanded………………………...………………..……..135
Figure 2.10: 6’,-Diguanidinoamikacin COSY…………………………..…………….136
Figure 2.11: 6’,-Diguanidinoamikacin COSY expnaded………………...…...……….137
Figure 2.12: Raw fluorescence data and normalized binding curve for amikacin……...140
Figure 2.13: Kanamycin-coumarin displacement curves………………..……………...141
Figure 2.14: Neomycin-coumarin displacement curves……………...………...………142
Figure 2.15: Parent aminoglycoside crystal structures………………...……………….145
Figure 3.1: Streptomycin………………………..……………………………………...149
Figure 3.2: Guanidinoglycosides…………………...……………………..……………150
Figure 3.3: Kanamycin-coumarin displacement curves………………..………………163
Figure 4.1: Tobramycin, amikacin, and derivatives………………..…………………..169
Figure 4.2: Crystal structures of tobramycin and amikacin with the A-site………...….170
Figure 4.3: Representative displacement curves of aminoglycoside-coumarins…….....175
Figure 4.4: Kanamycin-courmarin displacement curves…...…………………………..204
Figure 4.5: Neomycin-coumarin displacement curves……………...………………….205
Figure 5.1: TAN-1057 A/B……………………………………………………………..213
Figure 5.2: Aromatic TAN-1057 analogs…………………...………………………….214
Figure 5.3: Pyrimidinone cores………………...…………………………………….....216
Figure 5.4: Ureido-pyrimidinone dimers……………………...………………………..216
Figure 5.5: Crystal strucuture of (Boc)lysine-isocytosine………………...……………220
Figure 6.1: 3-Lysine containing natural products…………………………..…………242

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LIST OF SCHEMES
Scheme 2.1: Primary alcohol to guanidinium conversions………...…………………….94
Scheme 2.2: 6’’-Deoxy-6’’-guanidinoapramycin synthesis……………...……………...95
Scheme 2.3: Amine to guanidinium conversions………………..………………………96
Scheme 2.4: 6’’-Deoxy-6’’-guanidinotobramycin synthesis………………...………....108
Scheme 2.5: 6’’-Deoxy-6’’-guanidinoamikacin synthesis…………..………………....110
Scheme 2.6: 6’’-Deoxy-6’’-guanidinokanamycin A synthesis………………………....114
Scheme 2.7: 5’’-Deoxy-5’’-guanidinoneomycin synthesis…………...…..…………....117
Scheme 2.8: 5’’,6’-Deoxy-5’’,6’-guanidinoparomomycin synthesis………..………....119
Scheme 2.9: 6’’-Deoxy-6’’-guanidinoapramycin synthesis……...………………….....122
Scheme 2.10: 6’-Guanidinotobramycin synthesis…………………...…………………126
Scheme 2.11: 6’,-Diguanidinoamikacin synthesis…………………...………………..127
Scheme 3.1: Representative global amine to guanidinium conversion…...…………....151
Scheme 3.2: Guanidinostreptomycin synthesis……………...…………………………152
Scheme 4.1: Synthesis of key tobramycin intermediates……………………………….172
Scheme 4.2: Substitution reactions of 6’’-deoxy-6’’-
triisopropylbenzylsulfonyl(Boc) tobramycin…………………………………………..172
5
Scheme 4.3: Synthesis of 6’’-deoxy-6’’-ureidotobramycin…………………………….173
Scheme 4.4: Synthsis of 6’’-deoxy-6’’-(4-(aminomethyl)-1H-1,2,3-triazol-1-yl)-
(Boc) tobramycin………………………………………………………………………173
6
Scheme 4.5: Synthesis of key amikacin intermediates………………………………...193
Scheme 4.6: Synthesis of 6’’-deoxy-6’’-aminoamikacin……………………………....194
Scheme 4.7: Synthesis of 6’’-deoxy-6’’-methylaminoamikacin………………….…....195
Scheme 4.8: Synthesis of 6’’-deoxy-6’’-dimethylaminoamikacin………...…………...196
Scheme 4.9: Synthesis of 6’’-doexy-6’’-(2-(aminoethyl)amino)amikacin..……….…..198
Scheme 4.10: Synthesis of 6’’-deoxy-6’’-ureidoamikacin…………...…………….…..200
Scheme 4.11: Synthsis of 6’’-deoxy-6’’-(4-(aminomethyl)-1H-1,2,3-triazol-1-yl)-
amikacin………………………………………………………………………………...201
Scheme 5.1: BnU-Cyc synthesis………………………………………………...……...218
Scheme 5.2: Lys-BnU-Cyc synthesis………………………………..…………………218
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