新骨架类黄酮假鹰爪素衍生物的优化设计合成及其抗肿瘤机制研究

Des-B/Des-C, two novel natural products isolated from Desmos Lour, exhibited significant inhibition on the growth of human cancer cell lines in vitro and no overt toxcity in vivo (rats: LD50=46.0 mg/kg). In our previous studies, Desmosdumotins derivatives displayed potent inhibitory effect against multiple human tumor cell lines, and more significantly, they selectively inhibited P-gp overexpressing MDR KB-VIN tumor cell while was inactive against the KB cell line, showing a 460-fold KB/KB-VIN sensitivity. These novel chalcone/flavonoids derivatives contain a unique core scaffold with a non-aromatic trimethylated ring-A. Supported by National Natural Science Foundation of China, tremendous efforts were invested on the development of this new series as anti-cancer agents. The preliminary Structure-Activity Relationships (SARs) studies were conducted on ring A and ring B, and new potent and selective derivatives with improved pharmacological profiles were obtained. In this continuing study, we will continue the chemical modifications and SARs studies on their derivatives and establish effective synthetic methdologies toward to these new compounds, allowing the chemical modifications and parall synthesis feasiable. In addition, the Mechanism of Action (MOA) studies will be carried out using the active deriatives, which will lead to the discovery of new therapecutic with distinguished MOA for the treatment of cancer.

假鹰爪属植物中分离得到的天然新骨架类黄酮结构Des-B/Des-C体内外均表现出良好的抗肿瘤活性，且毒性低（LD50=46.0 mg/kg）。其衍生物对多种人属肿瘤细胞具有很强的抑制作用，同时对耐药肿瘤细胞KB-VIN具有高度选择性（ED50=0.03 μg/mL,KB/KB-VIN=460）。先导物具有独特的非芳香三烷基取代A环结构，为创新药的开发提供了新骨架结构。课题组在国家自然科学基金持续支持下做了大量研究工作，在前期研究基础上，对已有化合物进行构效关系分析，发现A环烷基链的延长以及在B环引入大位阻基团对活性提高有很大贡献，本课题结合这一结论进一步优化结构设计，开发多条简单便捷、有利于化合物大量获得的合成路线，得到系列衍生物进行抗肿瘤活性筛选；同时以优化之活性衍生物作为分子探针对其抗肿瘤作用及其逆转多药耐药机制进行深入研究，以期获得具有独特机理的新型高选择抗肿瘤候选药物。

新型结构的活性天然产物是创新药物先导物主要来源。本课题先后在相关三项国家自然科学基金支持下，以我课题组首次从民间药物假鹰爪属植物中提取分离得到的天然新骨架类黄酮结构抗肿瘤活性先导物Des-B/Des-C为研究基础。以Des-C A环长烷基链取代修饰为研究目标，以Des-C衍生物对A549肿瘤株的细胞毒活性数据（ED50）为构建3D-QSAR模型，对先导化合物Des-C的结构进行分子力学和动力学模拟，通过能量优化构象搜寻与分类，最后进行CoMFA分析，得到该分子的优势构象，据此设计合成了40余个具有高活性的目标分子。机制研究表明Des-C的A环衍生物TEP-11作用于HL-60细胞后，Fas、FasL表达率显著上升；Bax表达率明显上升，Bcl-2的表达率则明显下降，Bcl-2/Bax的比值下降。结果明白通过影响Fas/FasL、Bax/Bcl-2的表达而影响信号传导通路，诱导靶细胞的凋亡，从而发挥抗肿瘤作用；TEP-11作用于MCF-7细胞后，可诱导细胞凋亡并且能够显著抑制MCF-7中NF-κBP65阳性细胞率的表达，诱导凋亡的机制和下调了细胞中NF-κB表达有关，同时衍生物耐药菌株MCF-7/ADR也表现出了逆转潜力，由此我们相信，此类化合物非常有潜力开发成为全新结构，疗效确切，安全性高具有我国自主知识产权的一类抗肿瘤候选药物，为后续的临床应用解决临床实际需求提供一个可靠的参考。