以二酮酸酯作为锌离子结合基团的组蛋白去乙酰化酶抑制剂的设计、合成及生物活性研究  

Design,synthesis,and biological activities of histone deacetylase inhibitors with diketo ester as zinc binding group

作　　者：陆慧[1] 苏红[1] 杨波[2] 尤启冬[1] 

机构地区：[1]中国药科大学药学院药物化学教研室,江苏南京210009 [2]浙江大学药学院药理学系,浙江杭州310058

出　　处：《药学学报》2011年第3期293-298,共6页Acta Pharmaceutica Sinica

基　　金：国家"重大新药创制"科技重大专项(2008ZX09401-001;2009ZX09501-003);江苏省自然科学基金资助项目(BK2007171)

摘　　要：组蛋白去乙酰化酶(histone deacetylases,HDACs)抑制剂可以在转录水平上调控基因表达,导致肿瘤细胞生长停滞,诱导肿瘤细胞分化和凋亡。目前应用最为广泛的氧肟酸结构可以与活性口袋底部锌离子螯合从而竞争性地抑制HDACs的去乙酰化作用,但是氧肟酸结构存在代谢不稳定和选择性差的缺点难以成药。本文以二酮酸酯结构作为潜在的锌离子结合基团对氧肟酸进行替代,共合成了8个目标化合物,并对其HDACs抑制活性和对多种肿瘤细胞株的抗增殖活性进行了研究。其中化合物CPUYS707对人髓系白血病细胞株U937的抗增殖活性GI50达到0.31μmol.L-1,优于阳性对照药物SAHA和MS-275。Histone deacetylases（HDACs） inhibition causes hyperacetylation of histones leading to growth arrest,differentiation and apoptosis of tumor cells,representing a new strategy in cancer therapy.Many of previously reported HDACs inhibitors are hydroxamic acid derivatives,which could chelate the zinc ion in the active site in a bidentate fashion.However,hydroxamic acids occasionally have produced problems such as poor pharmacokinetics,severe toxicity and low selectivity.Herein we describe the identification of a new series of non-hydroxamate HDACs inhibitors bearing diketo ester moieties as zinc binding group.HDACs inhibition assay and antiproliferation assays in vitro against multiple cancer cell lines were used for evaluation.These compounds displayed low antiproliferative activity against solid tumor cells,while good antiproliferative activity against human leukemic monocyte lymphoma cell line U937.Compound CPUYS707 is the best with GI50 value of 0.31 μmol·L-1 against U937 cells,which is more potent than SAHA and MS-275.HDACs inhibition activity of these compounds is lower than that expected,further evaluation is needed.

关 键 词：组蛋白去乙酰化酶抑制剂 锌离子结合基团 二酮酸酯 

分 类 号：R916[医药卫生—药学]