传统中药千金子中Jokinol型二萜抗肿瘤多药耐药调控剂的研究

Multidrug resistance (MDR) is a challenge of cancer therapy, and there is no modulator available in clinical cancer therapy. Overexpression of ABC (ATP-binding cassette) transmembrane transporters are the key reason of MDR. The large volume of hydrophobic internal cavity in ABC transporters makes the contradiction between lipophilicity and druggability, and general expression in epithelial cell of tissues causes the side-effect problem. Natural products are the good source to seek the potential modulators of multidrug resistance due to their various structure types. Macrocyclic diterpenes accounting for 5% in Chinese traditional medicine QIANJINZI (seeds of Euphorbia lathyris), have always been mistaken for useless natural products. In our previous studies, Jokinol diterpene showed prominent potential, but it is low content. There is no report about the synthesis method of Jokinol diterpenes and systematic research of structure−activity relationship. We attempt to design and synthesize the Jokinol diterpene targeting conjugates to overcome the difficulties of MDR. According to our previous results of Lathyrol diterpenes, we plan to synthesize the Jokinol scaffold and the derivatives of Jokinol diterpenes from high content diterpenes in E. lathyris. Next, we will screen out the high activity compound as the drug efficacy part and synthesize the small molecular targeting conjugate. We intend to investigate their activities to ABC transporters and find effective modulators with development value for multidrug resistance of tumor.

多药耐药是肿瘤治疗的挑战，在癌症治疗的临床上仍没有成功使用的肿瘤多药耐药调控剂。过表达的ABC跨膜转运蛋白是产生MDR的关键原因，这类蛋白的巨大疏水空腔造成亲脂性和成药性的矛盾，体内组织表皮的广泛分布造成副作用难题。传统中药化学成分结构独特，另辟蹊径。千金子是我国传统中药材，大环二萜含量高达5%，一直被误认为是无用的天然产物。我们在筛选中发现，Jokinol二萜在逆转MDR上表现突出潜力，但是含量低，没有合成Jokinol二萜的方法和系统构效关系的报道。我们拟利用Jokinol二萜的靶向偶联物来克服MDR难题，从千金子中含量高的二萜出发，参考前期的Lathyrol二萜的研究结果，合成Jolkinol型母核，衍生得到系列Jolkinol二萜目标产物，筛选高活性化合物作为药效部分，连接为小分子靶向偶联物，评估其针对ABC跨膜转运蛋白的抗肿瘤多药耐药活性，发现具有开发价值的肿瘤多药耐药调控剂。

多药耐药是肿瘤治疗的挑战，在癌症治疗的临床上仍没有成功使用的肿瘤多药耐药调控剂。过表达的ABC跨膜转运蛋白是产生MDR的关键原因之一。千金子是我国传统中药材，大环二萜含量高达5%，一直被误认为是无用的天然产物。我们分别通过建立碱水解和路易斯酸衍生路线，合成系列3，5，7，15四个羟基位置不同取代变化、α，β-不饱和酮片段变化和环氧化衍生的二萜新衍生物37个，得到提取化合物5个，总计42个衍生物。全部开展细胞毒性测试，抗肿瘤多药耐药活性筛选，靶蛋白验证，机制验证，成效性分析，并阐明了系列衍生物的构效关系。25个衍生物具有比阳性对照维拉帕米（VRP）更强的逆转活性。其中，高活性的二萜化合物6个（Reversal Fold>20），优秀肿瘤多药耐药调控剂3个（Reversal Fold>400，EC50<5nM），分别为阳性对照VRP的218，229，454倍，并发现两个最高活性衍生物可以从根本上有效降低过表达P-gp蛋白表达水平的新机制。