中文摘要
齐墩果烷型皂苷是具有优良抗肿瘤活性的天然产物,日益受到研究者的重视。但其作用机制尚未明确,是目前亟待解决的科学问题。前期研究中,我们顺利合成了天然皂苷Albiziabioside A(AlbA);证明AlbA能够通过线粒体通路部分激活A375细胞发生凋亡作用;对AlbA进行结构改造取得了初步的构效关系。基于上述研究基础,我们进一步提出:①AlbA还可通过Ferroptosis途径导致A375细胞死亡;②将前期得到的活性优势片段结合,AlbA衍生物的抗肿瘤活性将进一步提高。针对上述假设,本项目拟通过荧光探针、分子生物学和细胞生物学技术验证猜想①;通过开展新一轮的结构修饰,进一步明确构效关系,证实猜想②。本项目的顺利实施有助于阐明齐墩果烷型皂苷的抗肿瘤作用机制,构建科学合理的Ferroptosis药物活性筛选体系,从而发掘结构新颖的具有Apoptosis/Ferroptosis双重激动剂。
英文摘要
In recent years, oleanane-type saponins, a large family of natural products, draw a lot of attention due to the excellent anti-tumor activity. However, the underlying mechanism is still unknown.. In our previous studies, we have efficiently synthesized albiziabioside A (AlbA) through a linear synthesis. Moreover, we confirmed that AlbA induce A375 cell apoptosis via mitochondria-mediated caspase cascade. Further, we performed structure modification of AlbA and got preliminary structure activity relationship (SAR).. Based on our previous observation, we further put forward the following conjectures: (1) To test if AlbA induces cancer cell death via ferroptosis, we will investigate the effect of AlbA on ferroptosis by fluorescent probe, molecular biology and cell biology techniques. (2) To investigate if antitumor activity of AlbA derivatives is improved by combination of excellent active groups, we will carry out structure modification to analysis SAR.. This study will provide a new insight into anti-tumor mechanism of oleanane-type saponins via apoptosis/ferroptosis double activation effects, and provide a screening system of ferroptosis for anti-tumor drug.
