基于中药活性成分金属抗肿瘤配合物研究

为改善金属抗肿瘤药物严重毒副作用和耐药性，拟针对雌激素受体或G-四链体DNA进行靶向设计以提高选择性；发挥中药活性成分(TCMAI)多样性和有效性及其与金属的协同作用,以提高其金属配合物的有效性；引入其它配体以降低系统毒性；发挥TCMAI－金属配合物的多靶点和多重作用机制以克服耐药性。选择中药活性成分氧化(异)阿朴菲为主要配体，采用上述策略，设计、合成雌激素受体调节或针对G-四链体DNA的TCMAI-铂、钌配合物。进行成药靶点和抗肿瘤活性筛选、裸鼠移植肿瘤有效性评价、PK-PD和毒理学研究。构建人血清白蛋白-TCMAI-金属药物多靶向载体，提高选择性和降低毒性。采用多种分析技术测定候选化合物在细胞中的作用成分、累积和分布。研究肿瘤细胞增殖周期和凋亡机制；利用基因芯片寻找肿瘤细胞死亡的相关基因和蛋白，用分子生物学方法验证关键作用靶点和通路。最终获得具有多靶点和多重作用机制的金属抗肿瘤配合物。

In order to improve the serious side-effect and resistence of metal-based antituour agents, we adopt the following strategies: 1）The selectivity is increased by targeting design basing on estrogen receptor or focusing on G-quadruplex DNA; 2) By means of exerting the diversity and validity of traditional Chinese medicines active ingredients (TCMAI) and their synergetic effect on metal, the validity of antitumour TCMAI-metal complexes is enhanced; 3) By introducing other ligands, the systemic toxicity is reduced; 4) In virtue of multi-target and multi-machanism of TCMAI-metal complexes, the resistence is overcomed. By selecting the traditional Chinese medicine active ingredient oxoaporphine and oxoisoaporphine alkaloids as main ligands and adopting mentioned above strategies, we design and synthesize TCMAI-Pt/Ru complexes targeting G-quadruplex DNA or having estrogen receptor regulating activity. We carry out the screen on druggable target and the assay of in vitro antitumour activity; The transplant tumour validity evaluation of candidates on SCID mouse model, the PK-PD study on the combination of pharmacokinetics (PK) and pharmacodynamics (PD) and toxicology are performed. Basing on the human serum albumin, we construct the multi-targeting carrier of TCMAI-metal-based drug. By meansi of many analytical techniques, the action components, accumulation and distribution of TCMAI-metal complex in cells are detected. We investigate the effect of candidates on the tumour cell cycle, and study the apoptosis mechanism of tumour cells. By gene-chip technique, the relevant proteins and genes on tumour cells death are found. We validate the key targets and pathways with modern molecular biology methods. Finally, the new highly active, low toxic antitumour TCMAI-metal complexes with multi-target and multi-mechanism are obtained.