中药活性成分及衍生物与第二信使供体协同调控Ru(II)化合物的诊疗活性研究

The Prodrug is one of decreasing side effects, the second messenger molecule is an effective way to enhance the sensitivity of drug-resistant cell lines, the synergistic effect of the active components and the metal base is an effective method to enhance the anticancer effect, the synergistic effect of active components of traditional Chinese medicine and metal is an effective method to enhance the anticancer effect, the fluorescence signal that changing with the release of the prodrug is an effective tool for aging diagnosis, Ru(II) multi-pyridine compounds have strong cytotoxic and diagnostic potential of fluorescent. Therefore, the complex prodrug of second messenger donor and the muti-pyridine Ru (II) -based compound of the traditional Chinese medicine have the potential to overcome the defects of clinical anticancer drugs. . we design and synthesize a series of the mercapto-mediated second messenger (NO/SO2) donors which can coordinate metal Ru(II) center with two sites firstly, then assemble into polypyridine Ru(II) complexes which are some precursor of multi-active-medicines with synthesized a series of isoquinoline alkaloids and second messenger (NO/SO2) donors. Through the invitro/vivo experiments against some tumor cell lines, several Ru(II) complexes (candidates) with high antitumor activity，good selectivity, theranostics activity are screened. At the same time, it,s tested that the reduction ability of candidates by enzymatic hydrolysis, and systematic anticancer mechanism against candidate complexes by molecular biology methods.

前药是降低毒副性的有效策略，第二信使分子是增强耐药细胞株敏感性的有效途径，中药活性成分与金属基的协同效应是抗癌增效的有效方法，伴随前药释放而变化的荧光信号是时效诊断性的有效工具，Ru(II)多吡啶类化合物具有较强的细胞毒和荧光诊断潜能, 因此第二信使供体与中药活性成分Ru(II)多吡啶类的复合前体化合物具有协同克服低效高毒、交叉耐药性及时效诊断性等多种临床缺陷的潜能。. 首先设计合成系列具有两齿螯合能力且由抗药性酶介导的第二信使(NO/SO2)供体，并用成熟方法合成系列中药活性成分及其衍生物(异喹啉类生物碱)，然后用第二信使供体与中药活性成分组装成系列具有诊疗活性潜能的Ru(II)多吡啶类化合物。通过体内外实验对目标化合物进行高效低毒性、耐药性、时效诊断性等性质进行综合评价和筛选，同时利用分子生物学方法对候选化合物的酶解还原能力及协同抗癌机制进行系统研究。

针对临床药物选择性差，耐药性及毒副性大的缺点，以中药活性成分氧化异阿朴菲生物碱为主配体，设计合成了系列结构多样性的金属有机Ru和Rh化合物，筛选出3个高细胞毒选择性、且具有诱导凋亡及免疫激活性能的候选化合物，其主要是通过增强免疫细胞浸润，肿瘤细胞的抗原呈递，改变肿瘤微环境等方面调控肿瘤免疫，这三个候选化合物具有较强的药用前景，为开发免疫激活性金属类药物奠定了理论和实验基础。结合金属有机化合物及异喹啉的生物活性特点，合成了8个类四氢异喹啉的金属有机化合物，筛选出了一个具有较强药用前景的双模式诱导细胞死亡的金属有机金化合物。以靶向策略设计合成了36个骨癌靶向性铂化合物，筛选出2个高细胞毒选择性、且具有诱导凋亡及免疫激活性能的候选化合物，这两个候选化合物具有较强的药用前景，为开发免疫活性铂类药物奠定了理论和实验基础。本项目共发表SCI论文7篇，申请发明专利4项，授权2项。参加国际国内学术会议3次，联合培养博士1名，培养硕士毕业生4名。