SYNTHESIS OF SMALL MOLECULE THERAPEUTICS UTILIZING RHODIUM CARBENOID CHEMISTRY Pubblico

Abstract

SYNTHESIS OF SMALL MOLECULE THERAPEUTICS UTILIZING RHODIUM CARBENOID CHEMISTRY

The primary objective of this thesis was to utilize the reactions of donor/acceptor substituted rhodium carbenoids for the synthesis of small molecule therapeutics.

The first major section of this thesis was devoted to explore a novel class of diarylcyclopropyl amines (CP-amines) as potential therapeutic agents for the treatment of cocaine addiction. A series of novel analogues were synthesized and a compound with 6 nM binding affinity towards 5HT2A receptor was identified. Extensive modeling studies have been performed to rationalize the existing activity trend among this novel class of CP-amines. The effects of selected CP-amines on cocaine self-administration in primates were also studied and preliminary in vivo data suggests that there is a considerable dose-dependent decrease in cocaine self-administration.

The second section of this thesis began with discovery of novel class of cyclopropane based SNRI's as potential therapeutic agents for the treatment of neuropathic pain. Over all, fifty novel compounds were synthesized. In vitro data showed a wide diversity of potencies and specificities at monoamine transporter sites. One of the lead compounds was found to be efficacious in reversing a symptom of neuropathic pain (mechanical allodynia) in nerve-injured rats. Extensive molecular docking studies were also performed.

The third section of this thesis began with a convergent approach to the total synthesis of 5-Z-7-oxozeaenol, a potent and selective TAK1 inhibitor. A library of over 45 novel acyclic RAL analogues was synthesized using carbenoid-induced ring- fragmentation of furans strategy. Many lead compounds were identified that showed sub µM inhibition of TAK1. These analogs were less toxic to normal cells and have higher tolerable dose. Few analogues showed decreased growth of human breast carcinoma xenograft in a mouse preclinical model without noticeable side effects.

In summary, we were able to initiate, execute and complete three different medicinal chemistry projects using enabling technology unique to Davies' group. Our multidimensional, multidisciplinary rational approach and collaborative efforts led to the discovery of three novel scaffolds for various targets, which might have a greater potential and broader impact in medication development for cocaine addiction, neuropathic pain and cancer.

Table of Contents

TABLE OF CONTENTS
CHAPTER 1: INTRODUCTION TO RHODIUM CARBENOID CHEMISTRY...1

1.1 REFERENCES...7

CHAPTER 2: SYNTHESIS, MOLECULAR DOCKING AND BINDING STUDIES OF NOVEL 5-HT2A RECEPTOR ANTAGONISTS - POTENTIAL THERAPEUTIC AGENTS FOR COCAINE ADDICTION...10

2.1 INTRODUCTION...10

2.1.1 Cocaine addiction...10

2.2 BACKGROUND...11

2.2.1 Neurotransmission and mechanism of action of cocaine...11
2.2.2 Animal model of cocaine addiction...13
2.2.3 Pharmacology of cocaine addiction...14
2.2.4 Serotonin ligands - Potential treatment agents for cocaine addiction...16
2.2.5 5-HT2A pharmacophore models...22
2.2.6 Bioactive cyclopropane compounds...24

2.2.6.1 SAR of trans aryl cyclopropylmethylamine compounds...27

2.2.7 Application of computational modeling in drug discovery and development...30
2.2.8 Previous synthesis of novel class of 5-HT2A receptor antagonists in the Davies group - Diaryl cyclopropylmethylamines...32
2.2.9 SAR of previously synthesized diaryl cyclopropylamines...37

2.3 RESULTS AND DISCUSSIONS...45

2.3.1 Synthesis of new series of diarylcyclopropylmethylamines - Lead optimization and activity trend rationalization...45
2.3.2 In vitro data for new series of diarylcyclopropylmethylamines...52
2.3.3 Reverification of the in vitro data...54
2.3.4 Computational modeling...59

2.3.4.1 Homology models of the human 5-HT2A receptor...60
2.3.4.2 Structural information about 5-HT2A and 5-HT2C receptor...62
2.3.4.3 5-HT2A and 5-HT2C receptor active site comparison...65
2.3.3.4 Ligand based approach...67
2.3.4.5 Receptor based approach...72
2.3.4.5.1 Docking of standard 5-HT2A and 5-HT2C ligands...74
2.3.4.5.2 Docking of HD-297 and HD-311 ligands...78

2.3.5 In vivo data for novel diaryl cyclopropylamine compounds...83

2.4 CONCLUSIONS...86
2.5 REFERENCES...88
2.6 EXPERIMENTAL SECTION...95

CHAPTER 3: SYNTHESIS AND DOCKING STUDIES OF NOVEL CLASS OF SELECTIVE SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS (SNRI'S) FOR THE TREATMENT OF NEUROPATHIC PAIN...137

3.1 INTRODUCTION...137
3.2 BACKGROUND...139

3.2.1 Monoamine reuptake inhibitors - classification...139
3.2.2 Milnacipran...145
3.2.3 Enantioselective synthesis of milnacipran...146
3.2.4 CNS drug development in the Davies' group...148
3.2.5 Intermolecular asymmetric catalytic cyclopropanation - An enabling technology for CNS drug development...155

3.3 RESULTS AND DISCUSSIONS...170

3.3.1 Synthesis of milnacipran analogues...170
3.3.2 In vitro data of milnacipran analogues...184
3.3.3 Synthesis of novel arylcyclopropylamines...186
3.3.4 In vitro data of novel aryl cyclopropylamines...188
3.3.5 Racemic synthesis of novel aryl cyclopropylamines...191
3.3.6 In vitro data of racemic aryl cyclopropylamines...195
3.3.7 Enantioselective synthesis of novel aryl cyclopropylamines...198
3.3.8 In vitro data of enantiopure aryl cyclopropylamines...207
3.3.9 In vivo data of aryl cyclopropylamines...211

3.3.9.1 Anti-allodynic effects of racemic cyclopropylamines as compared to clonidine...212
3.3.9.2 Anti-allodynic effects of enantiomers of 3,4-dichlorophenyl cyclopropylamines as compared to milnacipran...214
3.3.9.2 Effects of novel SNRI analogues on sedation and/or motor coordination in the rotarod assay...218

3.3.10 Computational modeling of SERT, NET and DAT...219

3.3.10.1 Structural information of SERT, NET and DAT...220
3.3.10.2 Initial XP docking of novel cyclopropylamines in SERT, NET and DAT...223
3.3.10.3 XP docking of novel cyclopropylamines in the refined models of SERT, NET and DAT...225
A) XP docking in SERT...226
B) XP docking in NET...228
C) XP docking in DAT...230

3.5 CONCLUSIONS...235
3.6 REFERENCES...236
3.7 EXPERIMENTAL SECTION...245

CHAPTER 4: SYNTHESIS OF TAK1 KINASE INHIBITORS AS POTENTIAL ANTICANCER AGENTS...345

4.1 INTRODUCTION...345

4.1.1 Cancer Therapy...345

4.2 BACKGROUND...347

4.2.1 Transforming growth factor-beta (TGF-β) and NFkB pathway in breast cancer...347
4.2.2. Resorcylic acid lactones (RALs) as TAK1 inhibitors...349
4.2.3 Total synthesis of 5-(Z)-7- Oxozeaenol...352
4.2.4 Carbenoid-induced ring-fragmentation of furans - A method for synthesis of acyclic RAL analogues...356
4.2.5 The mechanism of the furan unraveling reaction...361
4.2.6 Synthetic utility of the furan unraveling reaction...364

4.3 RESULTS AND DISCUSSION...365

4.3.1 First approach - Proposed convergent synthesis of 5-(Z)-7-oxozeaenol (4-3)...365
4.3.2 Second approach - synthesis of cis-enones using furan unraveling reaction...372

4.3.2.1 Synthesis of aryl diazoacetates...373
4.3.2.2 Reaction of aryl diazoacetate compounds with 2-methoxy furan...375
4.3.2.3 Synthesis of heteroaryl diazo compounds and their reaction with 2-methoxy furan...380
4.3.2.4 Synthesis of vinyl diazo compounds and their reaction with 2-methoxy furan...383
4.3.2.5 Synthesis of diazo ester derivatives, phosphonate diazo compound and their reaction with 2-methoxy furan...384
4.3.2.6 Reaction of methyl 2-diazo-2-(3,4-dichlorophenyl)acetate with various 2-substituted furans...387
4.3.2.7 Synthesis of diazoketones...389
4.3.2.8 Attempts to synthesize more elaborate dienones...392
4.3.2.9 Structural analysis of the products formed in furan unraveling reaction...396
4.3.2.10 Summary of In vitro evaluation of acyclic RAL Analogues...399
4.3.2.11 Summary of In vivo evaluation of lead compounds...403

4.4 CONCLUSIONS...404
4.5 REFERENCES...405
4.6 EXPERIMENTAL SECTION...406

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic Chemistry, Pharmaceutical Chemistry, General
Parola chiave	DIRHODIUM CATALYST TAK1 COCAINE ADDICTION CANCER TREATMENT COMPUTATIONAL MODELING CYCLOPROPANATION DOSP NEUROPATHIC PAIN 5-HT2A RECEPTOR ALLODYNIA RHODIUM CARBENOID 5-HT2C RECEPTOR ASYMMETRIC SYNTHESIS G-PROTEIN COUPLED RECEPTORS
Committee Chair / Thesis Advisor	Davies, Huw, Emory University
Committee Members	Snyder, James P, Emory University Liotta, Dennis C, Emory University Menger, Fred M, Emory University

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