- 學位論文
發展4,4’-亞甲基對苯胺或聯苯胺為骨架的四氯衍生物作為人類麩胺基硫轉移酶抑制劑的合成及構效關係的探討
Discovery, Synthesis and Structure-Activity Relationship of 4,4’-Methylenedianiline or Benzidine Based Tetrachloro Derivatives as Human Glutathione S-Transferase Inhibitors
摘要
抗藥性為癌症用藥在臨床上常遇到的問題。麩胺基硫轉移酶 (Glutathione S-transferase，GST) 在許多種癌細胞中大量表現的現象，被認為是癌細胞產生抗藥性的重要原因之一，因此設計並合成麩胺基硫轉移酶的抑制劑為本實驗的主要目的。 本實驗設計是由Ethacrynic acid為參考結構，以4,4’-亞甲基對苯胺 (4,4’-Methylenedianiline) 或聯苯胺 (Benzidine) 的四氯化合物為骨架，運用胺基與不同類型的結構形成二級胺或醯胺鍵結，包括含有雙鍵的脂肪族結構及含有雙鍵的芳香族或直接與芳香族鍵結。由於主結構中含有四個拉電子的Cl，使得胺基的親核性大幅降低，因此，選擇以醯氯作為合成醯胺鍵時的起始物，而在合成二級胺的過程中加入分子篩及TFA做為催化形成亞胺。目前已得到二十八個結構各異的化合物。 這些化合物在20 μM的濃度下對hGSTA2做初步的生物活性測試，結果顯示，A4-II、A8-II、A9-II、A15-II、B4-II、B8-II、B9-II、B15-II這些含有醯胺鍵的化合物擁有較好的抑制能力，推測羰基上的氧與酵素活化中心的氨基酸可形成氫鍵作用，因而增加了化合物與hGST A2的結合能力的緣故。此外A5-II和A6-II雖是二級胺化合物，但也有不錯的抑制能力。證明這類結構及其衍生物在生物體外確實具有抑制hGST的效果。
並列摘要
Drug resistance is a big problem in clinical therapy of anticancer drugs. The overexpression of glutathione S-transferase (GST) isozymes in number types of human cancers has been recognized as an important reason of drug resistance in cancer cell. Therefore, design and synthesis of the GST inhibitors are the targets of this thesis. The search of framework of GST inhibitor started at structural modification of ethacrynic acid. We chose both 4,4’-methylenedianiline and benzidine based tetrachloro compounds as the core structures, and used the amino group to form the secondary amine or amide linkage with different side chain including aliphatic or aromatic structure containing functional moiety of double bond. Because the four intramolecular Cl atoms are electron-withdrawing groups, they decrease the nucleophilicity of amino group in core structure. For this reason, acyl chloride was used as the reagent in amide bond construction in the presence of molecular sieve and TFA to facilitate imine formation in the first step of second amine synthesis. Twenty-eight derivatives have been prepared now and are ready for biological evaluation. Study of inhibitory activity showed that the amide compounds (20 μM), A4-II, A8-II, A9-II, A15-II, B4-II, B8-II, B9-II and B15-II display better inhibitory ability against hGSTA2 compared to those of the secondary amine derivatives. The results suggest that the oxygen of carbonyl group may increase the binding interaction with the amino acid residues of enzyme in the active site. Exceptionally, the secondary amine compounds, A5-II and A6-II, also exhibited moderate inhibition toward hGSTA2. In summary, these derivatives represent new chemical entities to inhibit hGST activity in vitro.
參考文獻
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