新穎組蛋白去乙醯酶分子探針之設計與合成

Abstract

組蛋白去乙醯酶 (histone deacetylase, HDAC) 催化組蛋白上離胺酸 (lysine) 側鏈的去乙醯基，與組蛋白乙醯轉移酶 (histone acetyltransferase, HAT) 相互拮抗調節染色質組蛋白的乙醯化程度，是參與表觀遺傳調控的重要因子。近年來許多研究發現，組蛋白去乙醯酶表現活性異常造成之蛋白質乙醯化程度失衡與許多疾病具有關聯性，如癌症、心血管疾病、神經退化性疾病、認知障礙、藥物成癮等。然而，現今對於這些人類疾病中正常組蛋白去乙醯酶的密度及活性的轉變過程仍不完全明確，因此正子斷層掃描造影技術之應用，提供了更為適切的直接、非侵入性醫學影像研究工具，用以即時監測染色質調控酵素在動物或人體內之分布、代謝情形。 本研究的目標為設計與合成一系列具新穎性之氟代烷基取代苯甲醯胺類結構之組蛋白去乙醯酶探針，並從中篩選出具有高活性及優良選擇性之最佳候選化合物，作為未來發展正子斷層掃描造影技術應用之分子探針。延續本實驗室過去之研究成果，經合成路徑及反應條件優化後，成功合成出具拉電子基修飾之苯環或芳香性雜環取代之化合物8、18系列衍生物，及不具N-甲基取代之化合物24系列衍生物，並建立了一條能夠快速、大量製備共同中間體並平行合成多個衍生物之合成路徑，可做為未來此系列化合物開發與合成之模板。

Histone deacetylase (HDAC) is responsible for removing acetyl groups from lysine side chain on histones and antagonizingly control acetylation of histone protein against histone acetyltransferase (HAT) which plays a critical role in chromatin modulation. Recently, an increasing number of researches have indicated that HDAC misexpression is related to a variety of diseases such as cancer, cardiovascular diseases, neurodegenerative diseases, cognitive impairment, and drug addiction. However, the knowledge of normal HDACs density and alterations in HDACs with human disease remains limited. Therefore, the non-invasive imaging technique, positron emission tomography (PET), is a valuable tool to visualize the real-time distribution and metabolism of chromatin-modifying enzymes in animals and human. The goal of this study is design and synthesis of a series of novel fluoroalkyl-substituted benzamide HDAC probes, and screening out the promising candidates for the development of HDAC molecular probes through pharmacological and physicochemical evaluation. As continuous efforts, a series of electron-deficient phenyl-substituted or heteroaromatic-substituted derivatives, compound 8, and 18 series, and a series of nor-derivatives, compound 24 series, were synthesized successfully with optimized yields. In addition, the modified synthesis pathway can be used for further studies of scale-up and parallel synthesis.