Nrf2/ARE信号通路与肺癌的发生、增殖及其耐药均密切相关，已成为肺癌化疗的新靶点。抑制该通路能够逆转肺癌耐药，从而增强化疗效果。本课题组研究发现，异喹啉类环金属化钌配合物（Cyclo-Ru-IQ）具有优异的抗肿瘤活性，能够逆转A549/DDP顺铂耐药，且可以下调Nrf2的表达。我们推测“Cyclo-Ru-IQ主要通过抑制Nrf2/ARE信号通路，逆转非小细胞肺癌顺铂耐药”。为证实此假说，本项目拟合成4个系列的Cyclo-Ru-IQ配合物，通过细胞实验及动物实验，检测其在体外、体内逆转非小细胞肺癌顺铂耐药的效果，并通过理论计算获取配合物的构效关系，指导优化分子设计；研究配合物对Nrf2/ARE上下游信号通路的调控，探讨并阐明其逆转非小细胞肺的顺铂耐药和抑制Nrf2表达的分子机制。项目的研究结果将为开发新型的Nrf2信号通路抑制剂提供理论依据，也为环金属化钌类抗肿瘤药物的开发提供新思路。

The latest findings show that Nrf2/ARE signaling pathway is closely related to the occurrence, proliferation and drug resistance of lung cancer, and has become a new target for lung cancer chemotherapy. Inhibition of this pathway can reverse lung cancer mutidrug resistance, thereby enhancing the efficacy of chemotherapy. Our previous studies suggested that cyclometallated ruthenium compounds equiped with isoquinoline derivatives (Cyclo-Ru-IQ) possessed obvious antitumor properties, could reverse A549/DDP cisplatin resistance and down regulate the level of Nrf2. Therefore, we speculate that “Cyclo-Ru-IQ could reverse non-small cell lung cancer(NSCLC) cisplatin resistance by inhibiting the Nrf2/ARE signaling pathway”. To confirm this hypothesis, in this project, four series of Cyclo-Ru-IQ will be synthesized firstly, and the inhibitory activity toward NSCLC cisplatin resistance cancer cells will be detected in vitro and in vivo through cell experiments and animal experiments. The structure-activity relationship which will be obtained through theoretical calculation further guide the optimization of molecular design. The effects of Cyclo-Ru-IQ on the upstream and downstream signaling pathways of Nrf2/ARE will be investigated, and the molecular mechanism of reversing NSCLC cisplatin resistance and inhibiting Nrf2 expression will be explored and elucidated. The results of these studies will provide a theoretical basis for the development of novel Nrf2 signaling pathway inhibitors and provide new ideas for the development of cyclometallated ruthenium antitumor drugs.