新型的双重应激靶向G-四链体DNA前药：药根碱水溶性抗肿瘤铂(II)配合物

为了改善抗肿瘤铂配合物的毒副作用大、生物利用度低和耐药性等问题，本项目拟在前期研究基础上，通过靶向性前药原理，以具有天然活性成分骨架和潜在抗肿瘤活性的中药活性成分药根碱衍生物为活性骨架，利用酯基（酰胺键）在肿瘤细胞微环境下释放的优势，将药根碱衍生物-铂(II)配合物设计成为一种能释放出活性铂(II)配合物和药根碱衍生物两种G-四链体配体的双重应激抗肿瘤药物，在一定浓度的过氧化氢介导下，以协同作用的方式增强了药物对肿瘤细胞的氧化应激能力，从而促进肿瘤细胞凋亡。通过铂(II)配合物的优化和设计，利用铂配合物与G-四链体DNA相互作用的多重结合模式，在分子水平上提高铂(II)配合物与G-四链体DNA的相互作用。通过体内外的抗肿瘤活性筛选和作用机制研究，最终获得以G-四链体为靶点的高抗肿瘤活性、低毒性、高选择性和特异性的新型金果榄中药活性成分药根碱水溶性金属抗肿瘤铂(II)配合物的药物释放前体。

In order to improve the serious side-effect, low bioavailability and resistence of platinum antitumor complex, jatrorrhizine base derivatives, which contain a natural active skeleton and have potential antitumor activity, are modified and then connected with ester functional group (eg. the amide bond), based on targeted prodrug principle and our previous research. Here we report a dual stimuli-responsive hybrid anticancer drug jatrorrhizine derivatives-platinum(II) complexes, which can be activated by hydrogen peroxide and acidic pH to release platinum(II) complexes and jatrorrhizine derivatives alkaloid G-quadruplex ligands as anticancer agents, respectively, in cancer cells. Consequently, these two G-quadruplex ligands act in a synergistic manner to amplify oxidative stress, leading to preferential killing of cancer cells in vitro and in vivo. By means of the optimization and design of these jatrorrhizine derivatives-platinum(II) complexes, utilization of various binding modes of platinum complexes interacting with G-quadruplex DNA we realize enhancing the interaction regulation and control of platinum(II) complexes and G-quadruplex DNA on molecular level. Finally, the novel water-soluble jatrorrhizine derivatives platinum(II) complexes ligands with high antitumor activity, low toxicity, high selectivity and specificity targeting G-quadruplex DNA will be obtained via the antitumor activity screening test and the physiological effects studies in vitro cytotoxicity and in vivo tumor growth inhibition activity.