EGFR/ErbB2双靶点抑制剂的设计、合成及生物活性研究

Tumorigenesis is always related to the structural and functional changes of several proteins. It is not enough to block the signal transition of tumour cells through single-targeted inhibitors, which sometimes have more side-effects and resistance. However, multi-targeted antitumor drugs may solve many problems of "targeting therapy". Hence, it is of great theoretical and practical significance to develop multi-targeted antitumor inhibitors. The dual EGFR/ErbB2 kinase inhibitors, Sorafenib and Sunitinib have good curative effects and little side effect in clinic. In this project, design, synthesis and bioactivities of dual EGFR/ErbB2 inhibitors will be studied by employing the multidisciplinary research techniques of computational chemistry, organic synthesis and biochemistry. The principles of bioisosterism and active substructure combination will be used to link thienopyrimidine and 1,3,4-thia(oxa)diazole. Based upon the interaction mechanisms between these molecules and EGFR/ErbB2, strategies will be proposed to design and synthesize dual EGFR/ErbB2 inhibitors, which will be excellent lead structures for novel antitumor drugs.

肿瘤的发生往往涉及多种蛋白结构和功能变化，试图通过单靶点药物阻断肿瘤细胞信号转导并不全面，有时副作用大，且易产生耐药性，而多靶点抗肿瘤药物可以解决"靶向治疗"的诸多问题。因此，研发不同结构类型的多靶点抗肿瘤抑制剂是一个具有重要理论与实际意义的研究课题。EGFR/ErbB2激酶双靶点抑制剂索拉非尼和舒尼替尼在临床上表现出了良好的疗效及较小的副作用，为此，本项目将综合运用计算化学、有机合成及生物化学等多学科技术，开展EGFR/ErbB2激酶双靶点抑制剂的设计、合成及生物活性研究。拟采用生物电子等排原理和活性亚结构拼接原理将噻吩并嘧啶与1,3,4-噻(噁)二唑进行连接，并系统性研究其与EGFR/ErbB2的相互作用机制，进而提出此类抑制剂的设计策略。在此基础上进一步设计并合成出结构全新的EGFR/ErbB2双靶点抑制剂，以期获得优异的先导结构，为开发新型抗肿瘤药物奠定基础。

本项目综合运用计算化学、有机合成及生物化学等多学科技术，开展EGFR/ErbB2激酶双靶点抑制剂的设计、合成及生物活性研究。运用生物电子等排原理、活性亚结构拼接原理以及生物合理设计等手段，设计并合成噻吩并[2,3-d]嘧啶类含氟衍生物、含1,3,4-噻(噁)二唑噻吩并[2,3-d]嘧啶化合物和噻吩并[3,2-d]嘧啶类化合物共226个，采用核磁共振波谱、质谱、X-射线单晶衍射和元素分析等方法进行了结构表征，并完成了其体外抗肿瘤活性测试。系统研究其构效关系，在此基础上结合计算机辅助分子设计技术，进一步设计合成，筛选出结构新颖的EGFR/ErbB2双靶点抑制剂，可作为优异的先导结构对其进行结构优化和改造，为开发新型抗肿瘤药物奠定基础。