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Design, Synthesis and Biological Evaluation of Novel Pin1 Inhibitors

Author: LiuChang
Tutor: FuDeCai；XuBaiLing
School: Hebei University of Science and Technology
Course: Medicinal Chemistry
Keywords: Pinl inhibitors Structure-Activity Relationship Quinazoline Diaryl ketone Anticancer drugs
CLC: TQ460.1
Type: Master's thesis
Year: 2011
Downloads: 24
Quote: 0
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Abstract


Pin1 (Protein interaction with NIMA1) discovered in 1996 , a new peptide prolyl cis -trans isomerase ( PPIase ) . The Han specificity of catalytic phosphorylation of Ser / Thr - proline -based sequence heterogeneous . Isomerization of this phosphorylation -dependent change of the conformation of the protein substrate , and to adjust their physiological functions . Pin1 over- expression in many tumor tissues , and there are a variety of cancer-promoting mechanism plays an important role in tumor development , are catalytic molecules known as tumor . Inhibit the the Pin1 expression or activity , can inhibit tumor occurrence and development . A large number of studies have shown that : Pin1 may become a new ideal anticancer drug target . Pin1 small molecule inhibitors to find a new structure , the paper carried out the following work : 1 , the paper summarizes the known Pin1 peptidomimetic inhibitors and small molecule inhibitors , combined with Pin1 complex crystal structure , summed up the the Pin1 inhibitor pharmacophore features by two hydrophobic center and a hydrogen bond or electrostatic interaction group . 2 This thesis is based on the pharmacophore model , design and synthesis of new compounds of the two types of structure . Total synthesis of a new structure of compound 54 , were identified by 1H-NMR , part of the compound was confirmed by ESI-HRMS . 3, using the the chymotrypsin coupling experiments , Pinl enzyme inhibitory activity of the 30 compounds was evaluated , and found that the new structure of the diaryl ketone compound 3 , the inhibitory activity of Pin1 in the micromolar level . 4 , the paper also carried out preliminary structure-activity relationship analysis prompted the introduction of diaryl ketone compounds A ring 5 - bit bulky aromatic hydrophobic segments help to improve the binding force ; ring B 3 - bit not the introduction of a large volume electron-donating group . The results of this thesis for further structural optimization, looking for the high activity of Pin1 small molecule inhibitors basis .

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