具有诱导肿瘤细胞凋亡和血管生成抑制双重作用的熊果酸类似物的设计、结构优化及类药性研究

The growth of solid tumors mainly depends on the tumor cells and the tumor vascular endothelial cells. Because of serious adverse reactions and drug resistance, the application of mainly cytotoxic chemotherapy drug has been largely restricted. The target of tumor angiogenesis inhibitors is tumor endothelial cells, so it rarely produces or does not produce resistance. Therefore, it is important to develop the new drugs which have the double-effect of induced apoptosis and tumor angiogenesis inhibitors role. Previous research using the natural product of ursolic acid as the lead compound, more than 300 derivatives have been designed and synthesised, of which more than 100 compounds exhibited significantly higher antitumor activity than ursolic acid, and the IC50 is about 0-10μ mol/L. Ursolic acid itself has the activity of inducing apoptosis of tumor cells and inhibiting angiogenesis, therefore, this researh will test the inducing apoptosis activity and inbibiting angiogenesis activity of active derivatives which we have synthesised. Based on this, we will prepare a series of new compounds by introducing active group to ursolic acid. This research combined the inducing apoptosis of tumor cells and inhibiting angiogenesis activities of nature product for the first time, it will provide an important foundation for new drug research and development. The idea of design and research is originality,and it will show good market prospects.

实体瘤的生长主要取决于肿瘤细胞和肿瘤血管内皮细胞，以细胞毒药物为主的化学疗法常因严重不良反应及耐药性使其应用受到很大限制，血管生成抑制剂作用靶点为肿瘤内皮细胞，很少产生或不产生耐药性。因此，开发具有诱导凋亡和抗血管生成双效作用的新药具有重要意义。前期研究以天然产物熊果酸为先导化合物，设计、合成共300 余个类似物，其中100余个类似物体外抗肿瘤活性显著高于熊果酸，IC50达到0-10μmol/L。熊果酸本身具有诱导肿瘤细胞凋亡及抑制血管发生作用，本项目计划对前期抑制活性显著的类似物进行抑制血管生长及诱导肿瘤凋亡活性研究；在此基础上，在熊果酸母体上引入活性基团，进一步制备新的、安全的、更高效的兼具诱导细胞凋亡/抑制血管生成的抗肿瘤化合物。本项目首次将血管生成抑制活性研究与诱导凋亡活性的天然产物研究紧密结合，为一类新药研制、开发奠定重要基础。该设计思想具有原创性，具有良好的市场前景。

实体瘤的生长主要取决于肿瘤细胞和肿瘤血管内皮细胞，以细胞毒药物为主的化学疗法常因严重不良反应及耐药性使其应用受到很大限制，血管生成抑制剂作用靶点为肿瘤内皮细胞，很少产生或不产生耐药性。因此，开发具有诱导凋亡和抗血管生成双效作用的新药具有重要意义。本项目以前期抑制活性显著的熊果酸类似物进行抑制血管生长及诱导肿瘤凋亡活性研究为基础，在熊果酸母体上引入活性基团，进一步制备新的、安全的、更高效的兼具诱导细胞凋亡/抑制血管生成的抗肿瘤化合物。在NSFC的资助下，课题组经过两年的研究，全面的完成了上述研究内容。通过对熊果酸等五环三萜类化合物进行开环、合环、糖苷化、成酰胺等修饰，最终合成了130余个结构衍生物。这些研究均取得了较好的成果，发现了一批具有良好细胞毒活性的五环三萜类衍生物。对其中活性良好的化合物的作用机制进行了初步的阐明，同时总结了部分化合物的构效关系。为开发五环三萜类类化合物的药用价值提供了新的思路。本项目有助于开发活性更理想的先导化合物，并为其他五环三萜类天然产物的结构改造提供新的思路。