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目的设计合成新型苯甲酰胺类组蛋白去乙酰化酶抑制剂,并探讨此类HDAC抑制剂的构效关系。方法以HDAC抑制剂恩替司他(entinostat,MS-275)为先导化合物,对其离子结合区与表面识别区进行改造,根据HDACs活性中心的结构特点,设计并合成了系列苯磺酰胺化合物。首先,对甲苯磺酰氯与邻硝基苯胺缩合得到含磺酰胺基的化合物,然后,经溴代、叠氮化、水解得到氨基化合物,最后与取代酰氯缩合并还原得到目标化合物。采用SRB法,对PC3、HL-60、A549三种肿瘤细胞株进行体外抗肿瘤活性筛选。结果与结论合成了11个未见文献报道的新化合物,化合物的结构经质谱、核磁共振氢谱、碳谱确证;体外抗肿瘤活性评价结果表明,化合物8j和8k对HL-60、PC3肿瘤细胞株具有增殖抑制活性,化合物8j对HL-60细胞抑制作用的IC50值为31.329μmol·L-1、化合物8k对PC3肿瘤细胞抑制作用的IC50值为3.612μmol·L-1。
Aim To design and synthesize novel benzamide histone deacetylase inhibitors and to explore the structure-activity relationship of such HDAC inhibitors. Methods The HDAC inhibitor entinostat (MS-275) was used as the lead compound to modify the ion-binding region and the surface recognition region. A series of benzenesulfonamide compounds were designed and synthesized according to the structural characteristics of HDACs. First, p-toluenesulfonyl chloride and o-nitroaniline condensation to give sulfonamide containing compounds, and then, by bromination, azidation, hydrolysis to give amino compounds, and finally condensation and reduction of acid chloride to give the target compound. The anti-tumor activity of three tumor cell lines PC3, HL-60 and A549 was screened by SRB method. RESULTS AND CONCLUSIONS Eleven new compounds were synthesized and their structures were confirmed by MS, 1HNMR and GC. The antitumor activity in vitro showed that 8j and 8k inhibited the proliferation of HL-60 and PC3 tumor cells The inhibitory activity of compound 8j against HL-60 cells was 31.329μmol·L-1. The IC50 of compound 8k against PC3 cells was 3.612μmol·L-1.