基于Bcl-2蛋白P2、P3活性区域抑制剂的设计、合成及体外活性研究

Design,synthesis and in vitro activity study of inhibitors based on the P2 and P3 active regions of Bcl-2 protein

目的探索Bcl-2蛋白P2、P3活性区域的构效关系,并设计合成活性较好的抑制剂。方法基于对Bcl-2蛋白抑制剂、Bcl-2蛋白P2、P3活性区域的分析,利用Autodock 4.2软件设计对接,合成一系列新型Bcl-2小分子抑制剂;采用MTT法测定所合成的抑制剂对人恶性黑色素瘤细胞A375、人肝癌细胞Hep G-2、人非小细胞肺癌细胞A549的体外抗肿瘤活性。结果合成了13个新型Bcl-2小分子抑制剂(D1~D13),其中,化合物D2、D6、D8的活性相对较好,对人恶性黑色素瘤细胞A375的抑制作用与阳性对照紫杉醇相当;化合物D1、D3、D4、D5也对A375细胞具一定的抑制活性。结论获得了P2、P3活性区域的构效关系,有助于Bcl-2蛋白抑制剂的进一步研究。

OBJECTIVE To obtain highly active Bcl -2 protein inhibitors by investigating the P2 and P3 active regions of Bcl -2. METHODS Based on analysis of the reported Bcl - 2 protein inhibitors and P2 and P3 active regions of Bcl - 2, a series of molecules were designed using Autodock 4.2 and then synthesized. Anti - tumor efficacy of these compounds on HepG - 2, A549, A375 cells were determined by MTI＂ assays in vitro. RESULTS Thirteen new compounds （D1 - D13 ） were synthesized. D1, D3,D4 and D5 exhibited mild anti - tumor efficacy on A375 ceil. D2, D6 and D8 displayed greater anti - tumor effects than other compounds, similar to that of Taxol. CONCLUSION The structure - activity relationship of the P2 and P3 active regions were obtained.