含丙二酰胺结构片段的硫醇类HDAC抑制剂的设计、合成及抗肿瘤活性研究  

Design,synthesis and antitumor activities of thiol-based HDAC inhibitors containing malonamide moiety

作　　者：王宛荞 杨金玉[1] 刘帅[1] 徐祺皓 牛群[1] 闻家辰[1] 赵临襄[1] 刘丹[1] 

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2015年第2期83-92,共10页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(81102323;81473086)

摘　　要：目的设计并合成含丙二酰胺结构片段的硫醇类HDAC抑制剂,评价其体外抗肿瘤细胞增殖活性及组蛋白去乙酰化酶抑制活性。方法以丙二酸二乙酯和1,5（6）-二溴戊（己）烷为原料,经C-烷基化、水解、缩合、亲核取代、水解共5步反应合成目标化合物;以伏立诺他为阳性对照药,分别采用MTT法和台盼蓝染色法考察了目标化合物对人乳腺癌细胞MCF-7和人急性早幼粒白血病细胞HL-60细胞株的抗增殖活性;并测试了部分化合物在10μmol·L^-1浓度下的抑酶活性。结果与结论共合成21个未见文献报道的新化合物,结构经1H-NMR、MS和IR确证;化合物Ⅲa-8、Ⅲa-11、Ⅲa-12、Ⅲa-13和Ⅲa-14的体外抗乳腺癌活性好于伏立诺他,其中Ⅲa-12的活性最强,IC50值为4.28μmol·L^-1,化合物Ⅲa-8的体外抗白血病细胞活性最强,GI50值为6.85μmol·L-1;Ⅲa系列化合物在10μmol·L^-1时的酶抑制率为59%~77%,而其相应的硫酯化合物没有表现出明显的酶抑制活性（抑制率〈5%）,说明硫酯类化合物不能直接与酶发生相互作用,而其水解产物具有一定的酶抑制活性。Based on previous research about ethanethioate derivatives containing malonamide moiety, a series of novel thiol-based derivatives containing malonamide moiety were designed and synthesized. Starting from diethyl malonate and 1,5 （ or 1,6 ） -dibromopentane （ or hexane）, followed by C-alkylation, hydrolysis, condensation, nucleophilic substitution and hydrolysis, twenty-one new compounds were synthesized. All the compounds were confLrmed by 1H-NMR, MS and IR spectrum. Preliminary structure-activity relationships were concluded. Take vorinostat as positive control, the antiproliferative activities against two cancer cell lines, MCF-7 and HL-60, were tested by MTT assay or trypan blue staining method. The antiproliferative assay suggested that compounds Ⅲa-8, Ⅲa-11, Ⅲa-12, Ⅲa-13 and Ⅲa-14 showed stronger potency against MCF-7 than vorinostat, compound Ⅲa-12 displayed the most promising activity with IC50 = 4. 28 μmol· L^-1. Ⅲa-8 showed good activity against HL-60 cells in vitro （GI50 -6. 85 μmol·L^-1）. HDACs enzyme inhibition activities of compounds Ⅱ-7 and Ⅲ a-3 at 10 μmol· L^- 1 concentration were screened. The inhibition ratio of Ilia series was 59% -77% ,while their corresponding thioate compounds had no obvious inhibition activity （inhibition ratio 〈 5 % ）, it showed that the thioate derivatives do not interact with the enzyme directly, while the corresponding hydrolysis products possess certain enzyme inhibition activities.

关 键 词：HDAC抑制剂 抗肿瘤活性 丙二酰胺 硫醇 化学合成 

分 类 号：R914[医药卫生—药物化学]