含吡嗪环的苯甲酰胺类HDAC抑制剂的合成及其抗肿瘤活性  

Design,synthesis and biological evaluation of benzamide derivatives containing pyrazine as histone deacetylase inhibitors

作　　者：徐佳彬[1,2] 万仁贵[1,2] 叶清泉[2] 赵砚瑾[2] 李庶心[2] 

机构地区：[1]江西中医药大学药学院,江西南昌330006 [2]军事医学科学院放射与辐射医学研究所,北京100850

出　　处：《中国药物化学杂志》2014年第5期351-357,共7页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(30772628)

摘　　要：目的设计合成具有抗肿瘤活性的新型苯甲酰胺类组蛋白去乙酰化酶抑制剂。方法 4-氨甲基苯甲酸酯化后与2,6-二氯吡嗪反应得到中间体,再经过Suzuki反应后与相应的取代苯硼酸偶联,在CDI的作用下与相应的苯胺反应得到目标化合物。结果与结论合成了12个未见文献报道的新化合物,其结构经MS、1H-NMR谱确证。化合物4a、4b、4d、4i和4k对人急性白血病细胞(HL60)和人乳腺癌细胞(M CF-7)的抑制活性与阳性对照物MS-275相比,活性相当或有较为显著的提高,可进行进一步研究。Histone deacetylase （HDAC） and histone acetyltransferase （HAT） are nuclear enzymes highly involved in the remodeling of chromatin. In normal cells, histone acetylation levels are determined by the competing activities of HDACs and HATs. HDACs catalyze the removal of acetyl groups from the lysine residues of the core histories and other proteins that control cellular functions such as proliferation, migration, differentiation and cell death. HDAC inhibitor has been considered as a very intriguing approach for cancer chemotherapy. In this study, a series of novel benzamide derivatives containing pyrazine as histone deacetylase inhibitors were designed based on the early work. The target compounds were obtained starting from 4- （aminomethyl） benzoic acid under esterification, nucleophilic substitution, Suzuki-Miyaura cross coupling and amidation reaction conditions. Their structures were identified by ^1H-NMR and MS, and the antitumor activities of the compounds were screened by MTT methods. The results indicated that five compounds （4a, 4b,4d,4i,4k） had potent antitumor activities which were more potent than their parent compounds. The most promising compound 4k showed a strong antitumor activity against HL60 and MCF-7 cell lines with GIs0 values of 0. 11 μmol. L^ - 1 and 0. 86μmol- L ^- 1, which were 9 to 40 times more active than the positive control （4. 49 μmol. L^-1,7.88 μmol. L^-1） , respectively. Further studies are currently underway and will be reported in the future.

关 键 词：苯甲酰胺衍生物 组蛋白去乙酰化酶抑制剂 吡嗪 

分 类 号：R914[医药卫生—药物化学]