設計與合成4-芳香基-1-苯甲基喹唑啉-2-酮類化合物作為第六亞型組蛋白去乙醯酶抑制劑之可行性

本論文主旨為設計與合成喹唑啉酮衍生物作為潛能第六亞型組蛋白去乙醯酶抑制劑及其相關活性研究。以喹唑啉-2-酮作為核心結構，並在其上加入該酵素表面作用官能基及鋅離子螯合基團。首先將鄰氨基苯甲腈與葛林納試劑經由親核加成反應後再與氯甲酸甲酯進行環化反應後得到帶有酵素表面作用官能基的喹唑啉-2-酮的主結構，之後將該主結構與帶有酯類官能基的側鏈接上，再將酯類官能基轉換成帶有酰基羥胺官能基之先導化合物22，最後，明確地找出對於不同的取代基所適合的不同路徑與其純化方法，希望能有利於後人減少開發路徑而可合成出更多更有效的目標化合物。根據酵素抑制與細胞毒性實驗，化合物22表現出顯著的第六亞型組蛋白去乙醯酶抑制活性 (HDAC6 IC50=6.5 nM, HDAC1 IC50=1930 nM) 及相較於第一亞型將近300倍的選擇性；然而先導化合物22則是對於一般的癌細胞不具毒殺性。由此先導化合物之結果，喹唑啉-2-酮之上方苯環區預期會暴露在酵素活性中心之外，且各亞型的組蛋白去乙醯酶在此區域之胺基酸序列差異性較大，故我們對於第4號位上的苯環區進行構效關係之探討而合成出目標化合物34a-b, 47a-b, 與49a-c。再根據酵素抑制與細胞毒性實驗，化合物34a表現出顯著的第六亞型組蛋白去乙醯酶抑制活性及最好的選擇性 (HDAC6 IC50=2.85 nM；HDAC6/HDAC1, 1004倍；HDAC6/HDAC8, 171倍)；然而已修飾過的目標化合物對於肺癌及大腸癌細胞具有較低的細胞毒殺效果。另外，化合物34a, 34b, 47b皆表現出一定程度的神經突觸活性、促進神經增生能力及神經軸突生長能力；然而在最大測試濃度25μM下並無發現神經細胞凋亡之現象。

關鍵字

組蛋白去乙醯酶抑制劑；喹唑啉-2-酮

並列摘要

The aim of this thesis is to design and synthetic a series of quinazolinone derivatives as potential selective histone deacetylase 6 (HDAC6) inhibitors. The quinazolin-2-one was employed as core structure tethered with surface contacting cap group and zinc binding group (ZBG). Initially, o-aminobenzonitrile was reacted with Grignard reagent by nucleophilic addition and then with methyl chloroformate by cyclization to give quinazolin-2-one core structures with surface contacting cap group. Then, these core structures were coupled with side chain containing ester function group through N-alkylation. Subsequently ester groups were transformed to hydroxamic acid as ZBG to give lead compound 22. Several approaches were developed to synthesize and purify target compounds with different function groups. On the basis of the result of enzyme-based and cytotoxicity assay, lead compound 22 showed significant enzyme inhibitory activity against HDAC6 and around 300 fold selectivity over HDAC1 (HDAC6 IC50=6.54 nM, HDAC1 IC50=1930 nM). However, compound 22 showed no cytotoxicity for general cancer cells. As these interesting results, 4-phenyl group of 4-aryl-quinazolin-2-one was presumed to be exposed out of HDAC active site and could influence its affinity with catalytic pocket, due to the amino acid differences of this region among HDAC subtypes. Further, to study SAR of 4-phenyl substitutions, we synthesized compound 34a-34b, 47a-47b, and 49a-c. From the result of enzyme-based and cytotoxicity assay, target compound 34a showed significant enzyme inhibitory activity against HDAC6 and also good selectivity (HDAC6 IC50=2.85 nM；HDAC6/HDAC1, 1004 fold；HDAC6/HDAC8, 171 fold). However, modification of compounds showed low cytotoxicity for lung cancer and colon cancer cells. In addition, compound 34a, 34b, 47b showed significant synaptic activity, neuroproliferation, and neurite outgrowth without neurotoxicity under 25μM.

並列關鍵字

HDAC Inhibitors ； quinazolin-2-one

參考文獻

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設計與合成4-芳香基-1-苯甲基喹唑啉-2-酮類化合物作為第六亞型組蛋白去乙醯酶抑制劑之可行性

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