Design, Synthesis And Biological Evaluation Of Novel Pin1 Inhibitors

Pin1 (Protein interaction with NIMA1) was 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 Pin1.1. Upon reviewing the known Pin1 inhibitors and the crystal structure of Pin1 complex with D-PEPTIDE, the pharmacophore model of Pin1 inhibitors was established. In this model, two hydrophobic groups and one hydrogen bond acceptor were hypothesized.2. According to the pharmacophore structure, a series of quinazoline compounds were designed and synthesized. Totally ninty two novel target compounds were obtained. All the target compounds were identified by 1H-NMR, some of them were further confirmed by ESI-HRMS.3. The binding affintiy of 29 compounds were measured and a novel series of quinazolines were found to inhibit Pin1 enzyme at micromolar level.4. The anticancer activities of the synthesized target compounds were evaluated on the various tumor cell lines with MTT assay and the structure-activity relationship analysis was carried out.5. The structure-activity relationship analysis has been carried out. The aromatic acid was introduced at 4-position and the hydrophobic aromatic group presented at the 2-position are favourable to the binding affinity. The 6-NO2 group had some contributions to the binding affinity as well. Compounds ZLN-418,ZLN-112 and ZLN-1127 are novel quinazoline Pin1 inhibitors. The further modification of these new Pin1 inhibitor lead structures might provide opportunity to access novel Pin1 inhibitors with improved anti-tumor activity and low toxicity.