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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 explore the structure-activity relationship of the active region of P2 and P3 of Bcl-2 protein and to design an inhibitor with good activity. Methods Based on the analysis of the active regions of Bcl-2 protein and P2 and P3 of Bcl-2 protein, a series of novel Bcl-2 small molecule inhibitors were designed and synthesized using Autodock 4.2 software. The synthesized inhibitors were determined by MTT assay In vitro antitumor activity against human melanoma A375, human hepatoma Hep G-2 and human non-small cell lung cancer A549. Results Thirteen novel inhibitors of Bcl-2 (D1 ~ D13) were synthesized. Compounds D2, D6 and D8 showed relatively good activity. The inhibition of A375 on human malignant melanoma cell line A375 was comparable to that of paclitaxel. Compound D1, D3, D4, D5 also have certain inhibitory activity on A375 cells. Conclusion The structure-activity relationship of P2 and P3 active regions is obtained, which is helpful for the further study of Bcl-2 protein inhibitors.