信号转导及转录激活因子3(STAT3)信号通路小分子抑制剂的设计、合成及其生物活性研究

Design, Synthesis and Biological Evaluation of Small-Molecule Inhibitors of Signal Transducer and Activator of Transcription 3(STAT3) Signaling Pathway

设计合成含有苯并噻唑及嘧啶并噻唑母核的化合物,评价其对信号转导及转录激活因子3(STAT3)信号转导通路的影响.以实验室前期报道的化合物16v为先导物,通过基于结构的药物设计及生物电子等排原理设计两个系列化合物.采用Luciferase法检测化合物对STAT3信号转导通路的影响.合成21个未见文献报道的新化合物,其结构经核磁共振氢谱、碳谱和质谱确证;Luciferase实验表明,苯并噻唑类部分化合物在10μmol·L-1浓度下能够很好的抑制IL-6刺激的STAT3信号转导通路,而嘧啶并噻唑类化合物活性较弱.

Constitutive activation of signal transducer and activator of transcription 3 （STAT3） is involved in the occurrence and development of the tumors, and is regarded as an attractive therapeutic target for cancer therapy. Our laboratory discovered some STAT3 inhibitors containing benzothiazole scaffold through virtual screening before. In a continuing effort to develop more potential STAT3 inhibitors, twenty-one target compounds based on our identified hit compound （16v） were rational designed and synthesized. These structures were characterized by 1H NMR, 13C NMR and HRMS. All the target compounds were tested for their inhibitory activity using a STAT3 luciferase reporter system. The results showed that many compounds displayed better activity than lead compound 16v in series I. However, compounds containing thiazolo[5,4-d]pyrimidine scaffold led to the loss of inhibitory activity. This may attributed to the losing of hydrogen bonding to Glu638.