Design, Synthesis And Biological Evaluation Of Novel Pin1 Inhibitors

Pin1 (Protein interaction with NIMA1) was first discovered in 1996, a new peptidyl prolyl cis-trans isomerase (PPIase), which specifically catalyzed the amide bond isomerization of phosphoserine-proline or phosphothreonine-proline in mitotic phosphoproteins. Pin1 induces the conformational changes to control the function of phosphoproteins. Pin1 is significantly overexpressed in many hunman tumor tissues, and there is a variety of tumor promotion mechanism. Pin1 plays an important role in the occurrence and development of tumors, which is known as tumor catalytic molecule. Depletion of Pin1 on various human cancer cell lines may inhibit tumor proliferation. A large number of studies have shown that Pin1 may become a novel promising anti-cancer drug target.In this thesis, the following work had been carried out in order to develop novel small molecular inhibitors of Pinl.1.Upon reviewing the known Pinl inhibitors and the crystal structure of Pinl complex with D-PEPTIDE, the pharmacophore model of Pinl inhibitors was established. In this model, two hydrophobic groups and one hydrogen bond acceptor were hypothesized.2.According to the pharmacophore structure, two series of new compounds were designed and synthesized.Fifty four novel target compounds were obtained in total. All the target compounds were identified by 1H-NMR, some of them were further confirmed by ESI-HRMS.3.The binding affintiy of 30 compounds were measured and a novel series of benzophenones were found to inhibit Pinl enzyme at micromolar level.4.The preliminary structure-activity relationships were analyzed. It has been demonstrated that the bulky aromatic motif on A ring of the benzophenones is favourable to the binding affinity and the bulky electron-donationg group is not tolerated on 3-positon of B-ring. The above results will provide some insight for the discovery of novel Pin1 inhibitors with improve acivities.