【摘要】 基于肿瘤、糖尿病等重大疾病的有限目标,选择蛋白酪氨酸磷酸酶(PTPs)家族这一生物体系中有代表性的PTP家族成员PTP1B,SHP-1,SHP-2,LAR,CDC25B及PRL-3进行研究.通过综合高通量筛选获得的"苗头"化合物结构信息,分析得到四氢喹啉骈环戊烯骨架.初步的构效关系研究表明,四氢喹啉酸骈环戊烯母核结构可作为PTPs抑制剂的基本骨架用于下一步的化学修饰.通过对34个化合物的设计、合成及构效关系的研究发现,四氢喹啉酸骈环戊烯的苯环8-位含有较大疏水取代基的化合物显示出对PTP1B较强的抑制活性和较高的选择性,其中,化合物31和35对PTP1B的抑制活性IC50分别达0.4和0.6μmol/L,并且对CDC25B,SHP1及SHP2显示出30倍以上的选择性.更多还原

【Abstract】 The protein tyrosine phosphatases(PTPs) constitute a family of closely related key regulatory enzymes that dephosphorylate phosphotyrosine residues in their protein substrates.Malfunctions in PTP activity are linked to various diseases,ranging from cancer to neurological disorders and diabetes.As part of a project aimed at identifying small molecular inhibitors based on PTPs family,focusing on diabetes mellitus,tumorigenesis,and infection,we performed the high-throughput screening(HTS) of a library of 48000 synthetic compounds for six representative PTPs,including PTP1B,SHP-1,SHP-2,PRL-3,CDC25B and LAR,and 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline analogues were identified as PTPs inhibitors.Keeping the core template complete,we began the modification of benzene ring,intending to find out the best modifying position in benzene ring and the proper amount of substitutions on it.Consequently,thirty-four compounds were designed and synthesized,and careful structure-activity relationship(SAR) study with respect to PTP1B,SHP-1,SHP-2,PRL-3,CDC25B and LAR was carried out.Finally,it was found that the compounds bearing a bulky substituent at 8-position of the cyclopentaquinoline acid turned out to be PTP1B inhibitors with good potency and selectivity against other assayed PTPs.The most potent PTP1B inhibitor in this series,compounds 31 and 35,show good activity(IC50=0.4 and 0.6 μmol/L,respectively) and excellent selectivity for PTP1B over SHP-1,SHP-2,PRL-3 and LAR,and 30-fold selectivity over CDC25B.Due to time limit,the modification of core template is not sufficient enough,and it would be the direction of our further work to discover more potent core structures.更多还原