약물설계를 위한 thiazolidinedione계 15-PGDH 억제제 합성 및 구조활성 분석 = Synthesis and structure activity relationship of thiazolidinedione derivatives as 15-PGDH inhibitors for drug design

국문 초록 (Abstract)

국문초록

약물설계를 위한 thiazolidinedione계15-PGDH 억제제 합성 및 구조 활성 분석

무 영
지도교수: 조훈
조선대학교 대학원 고분자공학과

Prostaglandins (PGs)은 prostaglandin endoperoxide를 거쳐 archidonic acid로 부터 합성되어진다. Prostaglandin E2 (PGE2)는 생리 및 병리학 측면에서 광범위하게 관여하고 있으며, 특히 PGE2는 생체 내에서 reproductives, gastromtestinal, nevroendocrine 및 면역시스템을 조절하는 중요한 역할을 담당하고 있다. 하지만 prostaglandin은 생체에서 15-hydroxyprostaglandin dehydrogenase (15-PGDH)에 의해 분해됨으로써 짧은 활성을 갖는다. Cytosolic 효소인 15-PGDH는 prostaglandin의 15-hydroxyl group을 ketone으로 변환시킴으로써 prostaglandin이 갖고 잇는 생리활성을 잃게 하는 기능을 갖고 있다. 따라서 이 효소의 활성을 억제하는 것은 PGE2 부족으로부터 유발되는 여러 가지 질병 치료에 사용이 가능할 것이다.
Thiazolidinedione 유도체인 5-(4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione （CT-8）은 전에 발표된 15-PGDH 억제제 중 하나이다. 구조-활성 분석결과 thiazolidine-2,4-dione의 아민 그룹에 methyl 그룹을 도입하게 되면 15-PGDH 억제효과를 잃게 되며, ethylhydroxyl 그룹을 도입할 경우에는 여전히 억제 효과를 가지고 있음을 보였다. Thiazolidinedione 유도체의 구조와 억제효과에 대한 상관관계 분석으로부터 보다 선택적인 화합물을 합성하기 위해 phenyl ring에 다양한 치환체를 도입 하였으며, 유도체에 대한 억제 활성을 평가하였다. CT-8 의 cyclohexylethyl group을 hetero five-member ring으로 치환할 경우여 활성이 증가하였다. 하지만 cyclohexylethyl group을 hetero six-member ring으로 치환할 경우에는 반대로 억제효능이 현저히 감소함을 보였다. 또한 phenyl ring에 –CH3, -OCH3, -OEt, -NO2, -CF3, -F, -Cl, -Br과 같은 그룹을 도입할 경우 15-PGDH에 대한 좋은 억제효과를 보였다. 그 중에서도 phenyl ring에 –Cl group을 포함하고 있는 43b 5-(3-chloro-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione 화합물이 nanomalar 범위에서 가장 강력한 억제효과를 보였다.

다국어 초록 (Multilingual Abstract)

ABSTRACT

Synthesis and structure activity relationship of thiazolidinedione derivatives as15-PGDH for drug design

Ying Wu
Academic Advisor : Prof. Cho Hoon, Ph. D.
Department of Polymer Science & Engineering,
Graduate School of Chosun University, South Korea

Prostaglandins (PGs) are derived from arachidonic acid through the prostaglandin endoperoxide synthase pathway. Prostaglandins have been implicated in a wide varity of physiological and pathological processes, Especially prostaglandin E2 (PGE2) regulated key responses in the major human systems including reproductives, gastrointestinal, neuroendocrine and immune systems. A cytosolic enzyme, NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of 15-(S) hydroxyl group of prostaglandins to 15-ketone, resulting in the biological inactivation of prostaglandins and a short life in vivo. Inhibitors of this enzyme will be valuable for the therapeutic management of many diseases.
Previously, 5-(4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione (CT-8), a thiazolidinedione analogue, was found to be a potent inhibitor of 15-PGDH. Structure-activity analysis indicated that the N-methylation of thiazolidine-2,4-dione of CT-8, abolished its inhibitory activity, whereas the introduction of an ethyl hydroxyl group at amine in CT-8 improved its inhibitory effect. Based on the structures of the thiazolidinedione analogues and inhibitory activities, a variety of benzylidene thiazolidinedione derivatives were synthesized with different substituents on the phenyl ring and then their inhibitory activities were evaluated. Replacement of the cyclohexylethyl group of CT-8 with the hetero five-member ring increased the inhibitory potency and cyclohexylethyl group was replaced with a hetero six-member ring was decreased the inhibitory potency significantly. Furthermore, compounds with substituents such as –CH3, -OCH3, -OEt, -NO2, -CF3, -F, -Cl and -Br on the phenyl ring were good inhibitors of 15-PGDH. It was found that the most active 15-PGDH inhibitors contain a -Cl group in the phenyl ring and compound 43b 5-(3-chloro-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione is the most effective potent inhibitor.

목차 (Table of Contents)

• CONTENTS
• List of Tables iii
• List of Schemes iv
• List of Figures v
• Abbreviations vi
• 국문초록..........................................................................................................................................viii
• ABSTRACT x
• 1. Introduction 1
• 1.1. Prostaglandins ...……1
• 1.1.1. Basic definitions 1
• 1.1.2. Biosynthesis of prostaglandins 1
• 1.1.3. Metabolism of PGE2...…………………………………………………………………..3
• 1.2. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) 5
• 1.2.1. Basic definitions 5
• 1.2.2. Function of 15-PGDH……………………………………………………………….......6
• 1.2.3. Three-dimensional structure of 15-PGDH 7
• 1.2.4. Reaction mechanism for 15-PGDH 9
• 1.3. Thiazolidinediones (TDs) 10
• 1.4. Necessity of 15-PGDH inhibitors 12
• 2. Results and discussion 14
• 2.1. Chemistry 14
• 2.1.1. Synthesis of compounds (1b - 36b) 14
• 2.1.2. Synthesis of compounds (37b - 50b) 14
• 2.1.3. Synthesis of compounds (51b - 57b) 15
• 2.1.4. Synthesis of compounds (78b - 92b) 15
• 2.1.5. Synthesis of compounds (93 - 98) 15
• 2.1.6. Synthesis of compounds (99 - 106) 16
• 2.1.7. Synthesis of compounds (107 - 109) 16
• 2.2. In vitro evaluation 16
• 3. Experimental 30
• 3.1. Materials and chemical agents 30
• 3.2. Expression and purification of 15-PGDH 30
• 3.3. 15-PGDH inhibitors activity assay 31
• 3.4. General procedure for the synthesis of compounds 31
• 4. Conclusion 104
• 5. References 106
• 1H NMR Spectra 118
• Acknowledgements 151