Design, synthesis and structure-activity relationship studies of bioactive ligands with heterocyclic scaffolds

다국어 초록 (Multilingual Abstract)

Design, Synthesis and Structure-Activity Relationship Studies of Bioactive Ligands with Heterocyclic Scaffolds

Duy-Viet Vo

Department of Pharmacy
Graduate School, Kangwon National University

Abstract

SECTION 1
Drug Development with Flavonol Scaffold as Chemotherapy-induced Peripheral Neuropathy (CIPN) Modulators

Currently, no sufficient treatment options are available for treatment CIPN; hence it is essential to find other safe and effective treatments. Natural products such as plant secondary metabolites are still important molecules of interest in the treatment of various pain conditions. The known in vitro and in vivo studies of CIPN therapeutics have shown flavonoids as the promising agents for the treatment of CIPN. The present research will focus on investigating the flavonoids, mainly flavonols, flavonol analogues and their derivatives with effects on CIPN.
We succeeded to design, synthesize a series of galangin analogues and their derivatives and evaluate their bioactivity against CIPN. We effectively developed a new method to synthesize the flavonol analogues via the nucleophilic substitution of the α-bromide compound and the Baker-Venkataraman rearrangement as key reactions with overall 6-8 steps and effective with high yield (~ 10%) from commercially available chemicals.
In our efforts to discover pharmacologically superior analgesic effects for the treatment of CIPN, we operated an approach to design the structure requirements for activity on CIPN. From the present SAR studies that we have the preliminary conclusions for the analgesic effect of flavonol’s for treatment CIPN. The result of this study will be helpful to amplify and comprehend the development of flavonols analgesic effects on CIPN.
Keywords: flavonol, galangin analogues, galangin derivaties, thioketones, nucleophilic substitution of α-ketone, Baker-Venkataraman rearrangement, analgesic effect, CIPN, SAR study, drug design.

SECTION 2
Drug Development with 1,3,5-Triazine Scaffolds as GPR119 Agonists

GPR119 is a G protein-coupled receptor (GPCR) expressed both in pancreatic β cells and enteroendocrine L cells. In vitro and in vivo studies show that GPR119 agonists can improve glucose homeostasis, proving GPR119 is a promising target for the treatment of type 2 diabetes. For the drug development study on GPR119, compound AR-231453 was chosen as the hit structure. The replacement of the 5-nitropyrimidine with less hepatotoxicity 1,3,5-triazine in parent rings was performed and assessed for their biological activity. Then two anilinos substituted by electron-withdrawing groups (EWG) were provided as tail moiety linked to the novel scaffold. Finally, replacement of the piperidine ring with conformationally controlled azabicyclic rings constructed a new series of 1,3,5-triazine analogues 2a-2l. We assessed the introduction of inflexible fragments like azabicyclic moieties to the ligands that decreased the conformational suppleness to create an ideal conformation and best recognized by the receptor.
We have also investigated synthetic pathway as a novel and stereoselective method of a series of key intermediate azabicyclic alcohols or amines 3a-3f in the good to excellent yields. In the synthetic strategy, dechlorination reaction with H2 and TEA, using 10% Pd/C as a catalyst in Et2O:THF to afford the target compounds 2a-2l was also studied as the key reaction. Nevertheless, the yield of the dechlorination reaction was not agreeable. Hence, the optimal conditions will be researched in subsequent studies to support the discovery of the lead compounds on 1,3,5-triazine scaffold for GPR119 agonist activity.
Keywords: GPR119 agonist, type 2 diabetes, 1,3,5-triazine, stereoselective of azabicyclic alcohols and amines, dechlorination, drug design.

목차 (Table of Contents)

• CONTENTS vi
• List of Abbreviations ix
• List of Figures xii
• List of Schemes xiii
• List of Tables xiv
• Abstract xv
• SECTION I
• Drug Development with Flavonol Scaffold as Chemotherapy-induced Peripheral Neuropathy (CIPN) Modulators
• CHAPTER 1. INTRODUCTION 2
• 1.1. Background of Chemotherapy-Induced Peripheral Neuropathy (CIPN) 2
• 1.2. Background of flavonoids and their effects on CIPN 5
• 1.3. Purpose of research 8
• CHAPTER 2. RESULTS AND DISCUSSION 9
• 2.1. Design of galangin analogues and their derivatives 9
• 2.2. Chemistry 10
• 2.2.1. Synthesis of 3,5,7-trihydroxy-2-phenyl-4H-chromen-4-one (Galangin) 10
• 2.2.2. Synthesis of Galangin analogues-I&II 12
• 2.2.3. Synthesis of Galangin analogues-III&IV 13
• 2.2.4. Synthesis of Galangin esters 15
• 2.2.5. Synthesis of Thiogalangin esters 16
• 2.3. Analgesic effects of synthetic flavonols 17
• 2.4. Structure-activity relationship (SAR) study of flavonols effects on CIPN 17
• CHAPTER 3. CONCLUSION 21
• CHAPTER 4. EXPERIMENTAL SECTION 22
• 4.1. Materials and Methods 22
• 4.2. Synthesis procedure of 3,5,7-trihydroxy-2-phenyl-4H-chromen-4-one (Galangin) 22
• 4.3. Synthesis procedure of 5,7-dihydroxy-3-mercapto-2-phenyl-4H-chromen-4-one (10) & -thione (11) 25
• 4.4. Synthesis procedure of 3-amino-5,7-dihydroxy-2-phenyl-4H-chromen-4-one (16) & -thione (17) 28
• 4.5. Synthesis procedure of galangin esters 32
• 4.6. Synthesis procedure of thiogalangin esters 35
• 4.7. Bioassays experimental for animal tests 37
• SECTION II
• Drug Development with 1,3,5-Triazine Scaffold as GPR119 Agonists
• CHAPTER 1. INTRODUCTION 41
• 1.1. Background of Type 2 Diabetes Mellitus 41
• 1.2. Background of GPR119 Agonists 44
• 1.2.1. The proposed Mechanism of GPR119 Agonist Action 44
• 1.2.2. Natural endogenous GPR119 agonists 45
• 1.2.3. Synthetic agonists of GPR119 46
• 1.3. Purpose of research 48
• CHAPTER 2. RESULTS AND DISCUSSION 49
• 2.1. Design of Novel GPR119 Agonists 49
• 2.2. Synthesis of GPR119 Agonists 50
• 2.2.1. Synthesis of azabicyclic alcohols and amines 3a-3e 50
• 2.2.2. Synthesis of 1,3,5-Triazine di-substitute target compounds 1a-1l bearing diverse azabicyclic alcohols and amines 51
• 2.2.3. Synthesis of 2,4-disubstitute 1,3,5-triazine target compounds 2a-2l bearing diverse azabicyclic alcohol and amine 52
• CHAPTER 3. CONCLUSION 54
• CHAPTER 4. EXPERIMENTAL SECTION 55
• 4.1. Materials and Methods 55
• 4.2. Synthetic Procedures of azabicyclic alcohols and amines 55
• 4.3. Synthetic Procedures of Target compounds 59
• REFERENCES 72
• ACKNOWLEDGEMENTS 82