新型一价金三唑类化合物诱导肿瘤细胞死亡的抗癌活性研究

Triazole is a kind of penta-hetercycles in which one carbon atom in imidazole ring is substituted by one nitrogen atom. Because triazole has less toxicity than imidazole and as pharmacophoric group，triazole ring exhibits various biological activities, therefore, triazole compound research has becoming one of the hot and key fields of medicine development in recent years. In addition, with the understanding of the cytotoxicity of the gold derivatives, the complexes containing gold are widely used as clinical drugs in treating tumors and other diseases. Hitherto, however, the study on biological activities of triazole-gold complexes has not been reported. Furthermore， dysregulated cell death is a common feature of many human diseases, and strategies aimed at modulating the associated pathways have been successfully applied to treat various disorders. From the point of the view of chemical biology, this project first utilizes novel gold(I)-triazole complexes as research tools to detect their effects on the survival, proliferation, migration, cell death in several cancer cell lines through various technologies and methods including MTT, EdU, flow cytometry, immunofluorescence, immunoblotting etc. This proposal focuses on the cell death patterns (apoptosis, autophagy and necrosis) by which the novel gold (I)-triazole complexes induce tumor cells death and determines their molecular targets, and thus finding the leading agents which have anti-cancer activities to prevent and treat various malignant tumor diseases.

三唑是咪唑环中的一个碳原子被氮取代得到的五元杂环。由于三唑环比咪唑具有更低的毒性，并且三唑环作为药效基团呈现出多种生物学活性，因此三唑类化合物已成为近几年来药物研究与开发的热点和重点领域之一。此外，随着对金类衍生物细胞毒性作用的不断了解，含金的化合物被广泛用作肿瘤以及其他疾病的临床治疗药物。但是迄今为止对三唑金类复合物的生物活性研究还未见报道。另外，细胞死亡紊乱是多种人类疾病的共同特征，因此调节相关的细胞死亡途径成为治疗多种疾病的策略之一。本项目从化学生物学的角度出发，首次以新型一价金三唑类化合物为研究工具，通过使用MTT法、EdU法、流式细胞仪、免疫荧光、免疫印迹等技术和方法，检测其对多种肿瘤细胞系存活率、增殖、迁移、死亡的作用，重点研究其诱导肿瘤细胞发生何种细胞死亡方式（凋亡、自噬和坏死）并确定其作用靶标，以期发现具有抗肿瘤活性可防治恶性肿瘤性疾病的先导药物。

目前，具有抗肿瘤活性的金属类化合物，特别是金类和铂类药物，在癌症治疗中发挥重要的作用。本项目以一价金（金诺芬）和二价铂（顺铂）化合物作为研究工具，通过使用CCK-8法、流式细胞仪、免疫印迹等技术和方法，研究其诱导HeLa细胞死亡的方式（坏死、凋亡、程序性坏死、自噬）。研究结果表明，金诺芬可通过多种方式诱导HeLa细胞死亡，包括：凋亡、坏死和自噬；而顺铂主要通过坏死和凋亡诱导HeLa细胞死亡。其中，首次发现金诺芬强烈诱导HeLa细胞自噬，并和凋亡及坏死协同促进HeLa细胞死亡。因此，金诺芬可作为重要的工具来研究HeLa细胞中自噬发生的关键分子，并阐明自噬和凋亡之间的相互作用关系；同时，增强自噬过程可促进HeLa细胞死亡，为宫颈癌的治疗提供了新思路和新策略。