新型含嘧啶环二芳基醚类Pin1抑制剂的设计、合成及活性评价

Design, synthesis and biological evaluation of novel diaryl ethers bearing a pyrimidine motif as human Pin1 inhibitors

Pin1是一种肽脯酰胺键异构酶(PPIase),是潜在的抗肿瘤药物靶标。本文基于二苯酮类Pin1抑制剂先导结构,设计合成了含有嘧啶环的二芳基醚类新结构化合物。采用胰凝乳蛋白酶偶联实验,评价了化合物5a～5d及6a～6i对Pin1酶抑制活性,发现了6个化合物对Pin1酶具有抑制活性。采用分子对接探索了上述化合物与Pin1的结合方式,为阐述构效关系和进一步结构改造提供了依据。

Pinl （peptidyl-prolyl cis-trans isomerase NIMA-interacting 1） belongs to peptidyl-prolyl cis-trans isomerase （PPIase） and is a novel promising anticancer target. Based on the lead structure of benzophenone, a series of novel diarylether derivatives containing a pyrimidine ring were designed and synthesized. The inhibitory activities on Pinl of compounds 5a-Sd and 6a-6i were evaluated by a protease-coupled enzyme assay. Of all the evaluated compounds, 6 compounds displayed inhibitory activities. Molecular docking was performed using FlexX algorithm to explore the binding mode of the active molecules.