高等学校化学学报 ›› 2011, Vol. 32 ›› Issue (2): 306.

• 研究论文 • 上一篇    下一篇

基于四氢喹啉酸骈环戊烯骨架的蛋白酪氨酸磷酸酯酶1B抑制剂的设计、合成及构效关系

柴茜1,沈强2,马兰萍1,王昕1,孟韬1,李静雅2,李佳2,沈竞康1   

  1. 1. 中国科学院上海药物研究所新药研究国家重点实验室,  
    2. 国家新药筛选中心, 上海 201203
  • 收稿日期:2010-05-04 修回日期:2010-08-16 出版日期:2010-02-10 发布日期:2011-02-23
  • 通讯作者: 马兰萍 E-mail:lpma@mail.shcnc.ac.cn
  • 基金资助:

    国家“八六三”计划项目(批准号: 2006AA02Z315)和上海市科学技术委员会基金(批准号: 08QH14005和08DZ2291300)资助.

Discovery and Structure-activity Relationships of Tetrahydro-3H-cyclopenta[c]quinolines Scaffold-based Potential PTP1B Inhibitors

CHAI Qian1, SHEN Qiang2, MA Lan-Ping1*, WANG Xin1, MENG Tao1, LI Jing-Ya2, LI Jia2, SHEN Jing-Kang1   

  1. 1.  State Key Laboratory of Drug Research,
    2.  The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203,  China
  • Received:2010-05-04 Revised:2010-08-16 Online:2010-02-10 Published:2011-02-23
  • Contact: MA Lan-Ping E-mail:lpma@mail.shcnc.ac.cn
  • Supported by:

    国家“八六三”计划项目(批准号: 2006AA02Z315)和上海市科学技术委员会基金(批准号: 08QH14005和08DZ2291300)资助.

摘要: 集中肿瘤、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,初步的构效关系确认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34个化合物的设计、合成及构效关系研究 ,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的抑制活性分别达到0.4 μmol/L和0.6 μmol/L(IC50),并且对CDC25B及SHP1、SHP2显示出30倍以上的选择性.

关键词: 蛋白酪氨酸磷酸酶(PTPs), 高通量筛选(HTS), 四氢喹啉酸骈环戊烯, 抑制剂

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 48,000 synthetic compounds for six representative PTPs, including PTP1B, SHP1, SHP2, PRL3, 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 begin 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 have been designed and synthesized, and careful SAR study with respect to PTP1B, SHP1, SHP2, PRL3, CDC25B and LAR was carried out. Finally, it has been 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, compound 31 and 35, showed good activity (IC50=0.4μmol/L and 0.6μmol/L, respectively) and excellent selectivity for PTP1B over SHP1, SHP2, PRL3 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.

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