New Pin1 Small Molecule Inhibitors Of The Design, Synthesis And Structure-activity Relationship Studies

Pinl is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase,which specifically catalyzes 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 different human cancer cells such as prostate,cervical,lung,hepatic,brain tumors and melanoma etc.Depletion of Pin1 on various human cancer cell lines cause mitotic arrest and apoptosis.Pin1 is an attracting therapeutic target for anticancer and its inhibitors might be potential anticancer drug.In this thesis,the following work had been carried out in order to develop novel small molecule inhibitors of Pin1.1.Upon reviewing the known Pinl 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 a hydrogen bond acceptor were hypothesized.2.The two key intermediates cis-and trans-3-(3,4-dihydroxybenzyl)-hexahydroprrolo-[1,2-a]pyrazine-1,4-dione were efficiently prepared in solid phase under microwave irradiation.3.The key intermediate 2,4-dichloro-6-nitroquinazoline was obtained in one-pot reaction. In comparison with literature work,this protocol leads to operational simplicity,small amount of urea and improved yields.4.Three series of target molecules,including piperizine 1,4-diones,pyridazinones and quinazolines,were designed and synthesized.Total seventy novel target compounds were obtained.All the target molecules were identified by ¹HNMR,and some of them were further confirmed by HRMS,¹³CNMR and NOE experiment.5.The anticancer activities of the synthesized target compounds were evaluated on the various tumor cell lines with MTT assay.Five compounds effectively inhibited the growth of tumor cells with IC₅₀ values of micromolar level.The structure-activity relationships of synthesized compounds provide some insight for design of new compounds with improved activities.