（+）-去氧娃儿藤宁新型衍生物的设计、合成及抗恶性脑瘤活性研究

Malignant cerebroma is one of the severe diseases that threaten human health with increasingly morbidity. There is a clinical need to develop anticancer drugs with new chemical structure and new mechanism to cure this disease. Natural products are major resources of leading compounds with anticancer activity. (+)-Deoxytylophorinine, a natural product that isolated in our laboratory, is a potent anti-tumor agent. Since this compound could pass through the blood-brain barrier in pharmacokinetic study, it could be used to treat malignant cerebroma. However, (+)-deoxytylophorinine displayed some toxicity in animal test. Therefore, it is important to discover the compound with higher activity and lower toxicity based on the SAR results in our previous work. Six classes of derivatives will be designed, synthesized and screened both in vitro and in vivo. The new SAR would be summarized and deeper mechanism would be studied. By evaluation of the toxicity and pharmacokinetic character of highly active derivatives, we expect to find new compounds with anti-malignant cerebroma activity.

恶性脑瘤是危害人类健康的疾病之一，发病率逐年增加，临床上需要研发新结构的、新机制的抗恶性脑瘤药物。天然产物是抗肿瘤活性先导物的重要来源，本项目是基于前期工作中所发现的具有抗肿瘤活性的先导物（+）-去氧娃儿藤宁，通过药代动力学研究发现其可以顺利透过血脑屏障，因此可以用于治疗恶性脑瘤，动物实验表明先导物具有一定的毒性，出于保持或提高活性、降低毒性的目的，在前期总结的构效关系的基础上，本项目拟对先导物进行进一步的结构修饰，设计了六类先导化合物的衍生物，通过对衍生物进行体外和体内活性筛选，对高活性化合物进行毒性及药代动力学研究，并进一步总结构效关系、研究其作用机制，期望发现具有抗恶性脑瘤活性的新型化合物，为抗恶性脑瘤新药的研发奠定基础。

恶性脑瘤是危害人类健康的疾病之一，发病率逐年增加，临床上需要研发新结构的、新机制的抗恶性脑瘤药物。天然产物是抗肿瘤活性先导物的重要来源，本项目是基于前期工作中所发现的具有抗肿瘤活性的先导物（+）-去氧娃儿藤宁，通过药代动力学研究发现其可以顺利透过血脑屏障，因此可以用于治疗恶性脑瘤，动物实验表明先导物具有一定的毒性，出于保持或提高活性、降低毒性的目的，在前期总结的构效关系的基础上，本项目设计合成了34个衍生物，通过对衍生物进行体外和体内活性筛选，对高活性化合物进行毒性及药代动力学研究，发现化合物3具有显著地抗恶性脑瘤的作用，且毒性较低，具有开成一类抗脑瘤新药的潜力。