2-(2-取代苯基)噻唑-4-(甲)乙酸类化合物的设计、合成及抗肿瘤活性

Design,synthesis and anti-tumor activities of 2-(2-substituted phenyl)thiazole-4-alkanoic derivatives

目的为了寻找有效的Pin1小分子抑制剂,以2-苯基咪唑-4-甲酸为先导化合物,设计并合成了18个2-(2-取代苯基)噻唑-4-(甲)乙酸类化合物8a-8r。方法以2-甲氧基苯甲酸为起始原料,经8步反应得到目标化合物;利用已建立的酶活性筛选平台测试了目标化合物浓度为10μmol·L-1时对Pin1酶的抑制率;采用MTT法,考察了目标化合物对人前列腺癌PC-3细胞的生长抑制作用。结果与讨论合成了18个未见文献报道的化合物,其结构经1H-NMR谱和MS谱确证;多数化合物具有Pin1抑制活性,其中化合物8 h的抑制率达到100%;化合物的整体细胞生长抑制作用较弱,化合物8 c和8 g对PC-3细胞具有中等生长抑制作用。

Objective Taking 2-phenylimidazole-4-formic acid as the lead compound,eighteen 2-(2-substituted phenyl)thiazole-4-alkanoic acid derivatives 8 a-8 r were designed and synthesized in search of effective Pin1 small molecule inhibitors.Methods Target compounds were synthesized in eight steps starting with 2-methoxybenzoic acid.Pin1 enzyme inhibiting activities of the target compounds were screened at 10μmol·L-1 using the establishedenzyme activity screening platform.The antiproliferative activities of target compounds against PC-3 tumor cell lines were evaluated by MTT methods.Results and Conclusion Eighteencompounds were synthesized,and their structures were confirmed by 1H-NMR and MS.The results showed that most compounds had Pin1 inhibitory activities,and compound 8 h totally inhibit its activity at 10μmol·L-1 among them.MTT assay indicated that compounds failed to exhibit any pharmacological activities,compounds 8 c and 8 g showed appropriate proliferation inhibitory activities in PC-3 cell lines.