藉著熱裂解二聚體生成6,6-二甲氧基環己-2,4-二烯酮新PPAR 抑制劑當作抗糖尿病試劑的設計與合成

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研究生：	紀森多士 Chittimalla Santhosh Kumar
論文名稱：	藉著熱裂解二聚體生成6,6-二甲氧基環己-2,4-二烯酮新PPAR 抑制劑當作抗糖尿病試劑的設計與合成 PartI: The Diels-Alder Reactions of 6,6-Dimethoxycyclohexa-2,4-dienones Generated by Pyrolysis of their Dimers; PartII: Design, Synthesis and In Vitro Studies of Novel PPAR Agonists as Anti-Diabetic Agents
指導教授：	廖俊臣 Liao, Chun-Chen
口試委員:
學位類別：	博士 Doctor
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2004
畢業學年度：	93
語文別：	英文
論文頁數：	212
中文關鍵詞：	掩飾鄰苯醌、骨牌反應、第二類糖尿病、新PPAR 抑制劑
外文關鍵詞：	Domino Reactions, Type 2 Diabetes, Novel PPAR Agonists
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中文摘要
論文包含兩個部份：
第一部份可分為兩個章節。第一章對本實驗室長期鑽研的掩飾鄰苯醌
(masked o-Benzoquinones)及其Diels-Alder 反應作文獻的整理及介紹；第二
章則探討本論文研究中關於：retro-Diels-Alder 同步進行Diels-Alder 反應的
應用，利用高溫條件下使掩飾鄰苯醌的雙聚物裂解後，同步與數種不同親
雙烯劑進行Diels-Alder 反應而得到多樣化的雙環[2.2.2]辛烯酮類化合物。
這樣的合成方法展現出三個優勢：(1)掩飾鄰苯醌的雙聚物在本實驗室以往
的結果中，一向是掩飾鄰苯醌與親雙烯劑行Diels-Alder 反應的副產物，而
這個副產物則經由此方法可以再被使用; (2)部份無法被合成或產率不高的
掩飾鄰苯醌及親雙烯劑Diels-Alder 產物可以經由這個方法達到提升產率的
效果；(3)可有效減少本實驗室在之前的合成研究中的Diels-Alder 反應的步
驟，增進合成的效能。
第二部份則包含兩個章節。第三章首要介紹糖尿病與過氧增生活化受
體(Peroxisome Proliferator Activated Receptors, PPARs)之關係；最後一章從
設計及合成的角度出發，以具有生體內(in vivo)生理活性之PPARs 相關化
合物作為抗糖尿病藥物的基底，由探討藥理活性的角度針對不同的取代基
(Ligand)進行合成。而在完成一系列藥物分子的合成之後，以之進行生理活
性的測試- 包含Scintillation Proximity Assay (SPA) 的IC50 測試、
Transcriptional Activation Assay (TA)的EC50 測試。而在一系列的測試之後，
發現化合物6e 具有成為藥物的潛力，目前正在進行更進一步的生理活性測
試(利用KKAy mice models)。

ABSTRACT
This thesis consists of two parts
Part I, gives a brief introduction of Diels-Alder reactions and masked
o-benzoquinones and contains the results and discussion along with the experimental
section of the novel domino retro-Diels-Alder (rDA) – Diels-Alder (DA) protocol
applied to the masked o-benzoquinone chemistry for the synthesis of several
bicyclo[2.2.2]octenones and bicyclo[2.2.2]octadienones. This procedure is focused
on 3 main objectives: 1) utilization of a masked o-benzoquinone dimer which was a
side product in the masked o-benzoquinone Diels-Alder chemistry; 2) increase the
yield of the Diels-Alder adducts which were difficult or not possible to synthesize by
earlier procedures; 3) decrease the number of synthetic steps to achieve the desired
Diels-Alder adducts which previously needed more steps.
Part II, gives a brief introduction of diabetes and peroxisome proliferator activated
receptors (PPARs) and the “Design, Synthesis and In Vitro Studies of Novel PPAR
Agonists as Anti-Diabetic Agents” and includes the experimental section of the present
work. A knowledge based drug design is used for synthesizing these novel ligands.
After successfully preparing several molecules, bioassay was conducted and IC50
[using Scintillation Proximity Assay (SPA)] and EC50 [using Transcriptional Activation
Assay (TA)] were obtained for all the compounds. Compound 6e was identified to be
potent PPARα,γ dual agonist and is presently under in vivo studies (KKAy mice
models).

Table of Contents
Dedication
iii
Acknowledgements
iv
Table of Contents
viii
List of Abbreviations
xiii
List of Few Important Figures
xvi
List of Publications
xvii
Part I
The Diels-Alder Reactions of 6,6-Dimethoxycyclohexa-
2,4-dienones Generated by Pyrolysis of their Dimers
1. Introduction and Background
1.1. The Diels-Alder Reaction and its Applications in Organic Synthesis
1
1.2. Retro-Diels-Alder Reaction and its Applications in Organic Synthesis
7
1.3. Masked o-Benzoquinones
1.3.1. Masked o-Benzoquinones in Diels-Alder Reactions 14
1.3.2. Masked o-Benzoquinones in Natural Product Syntheses 15
1.3.3. Dimerization of Cyclohexa-2,4-dienone Systems 16
1.3.4. A Detour Method for Improving the Yields of MOB Diels-Alder
Adducts
20
1.4. Domino rDA-DA Strategy in Organic Synthesis
21
1.5. Objectives
27
2. Results and Discussion
2.1. Standardization of Domino rDA-DA Reaction
28
2.2. Various Dienophiles in rDA-DA strategy (both bearing a Electron-
Withdrawing and Electron Donating groups)
29
2..3. Domino rDA-DA Reactions with Unreactive Dienophiles
37
2..4. Domino rDA-DA Reactions with Acetylenic Dienophiles
2.5. A kinetically controlled Domino rDA-DA reaction
38
41
2..6. Domino rDA-DA Reactions of Dimer 110a
41
2..7. Attempted Domino rDA-DA Reaction of Dimer 110a with
Dienophiles 111p and 111q
43
2.8. Structural Determination
46
2.9. Conclusions
53
2.10. Experimental Section
55
2.11. References
77
Part II
Design, Synthesis and In Vitro Studies of Novel PPAR
Agonists as Anti-Diabetic Agents
3. Introduction and Background
3.1. Insulin and its Function in Glucose Metabolism 81
3.2. Types of Diabetes 84
3.3. Therapeutic Intervention for Hyperglycemia
3.3.1. The α-Glucosidase inhibitors 87
3.3.2. The Sulfonylureas 87
3.3.3. The Biguanides 88
3.3.4. The Thiazolidinediones 89
3.4. Need for New Diabetes Drugs 91
3.5. Peroxisome Proliferator Activated Receptors 92
3.5.1. PPARα agonists 96
3.5.2. PPARδ agonists 97
3.5.3. PPARγ agonists 99
3.5.4. PPARα/γ dual agonists 100
3.5.5. PPAR α/γ/δ (pan) agonists 102
3.6. Objectives 104
4. Results and Discussion
41. Designing of Novel PPAR Ligands 105
4.2. Synthesis Heterocyclic Rings for PPAR Ligands 108
4.2.1. Synthesis of 3-Phenylbenzisoxazole Derivative 109
4.2.2. Synthesis of 3-Phenylbenzofuran Derivative 110
4.2.3. A Novel Rearrangement Reaction Leading to a 2-Phenylbenzo- furan
Derivative
112
4.2.4. Synthesis of 2-Phenylindole Derivative 116
4.2.5. Preparation of Scaffolds 120
4.3. Synthesis of Novel PPAR Ligands
4.3.1. PPAR Ligands with Carboxylic Acid group at O-end 121
4.3.2. PPAR Ligands with Carboxylic Acid group at N-end 125
4.4. PPAR Ligands based on MOB Chemistry
4.4.1. PPAR Ligand With MOB based Scaffold 126
4.4.2. PPAR Ligands With MOB based Building Blocks 127
4.5. Structural Determination 131
4.6. In Vitro Studies
4.6.1. Scintillation Proximity Assay (SPA) 132
4.6.2. Transcriptional Activation Assay (TA) 133
4.6.3. In vitro data for Compounds 6b, 6c, 6d, 15d, 21d, 22d, 34d 135
4.6.4. In vitro data for Compounds 6e, 15e, 21e, 22e, 34e 136
4.6.5. In vitro data for Compounds 6f, 15f, 21f, 22f, 34f 138
4.6.6. In vitro data for Compounds 6a, 6g, 62a, 69a 139
4.7. Conclusions 140
4.8. Experimental Section 141
4.9. References 207
Appendix One: 1H NMR Spectra Relevant to Chapter Two 1-22
Appendix Two: 1H NMR Spectra Relevant to Chapter Four 23-85

                                

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