膀胱癌治疗中吡柔比星等效果不佳，其它诸多化疗药物或因水溶性过低无法灌注给药，亟待研究开发可高效杀灭癌细胞，毒副作用低，制剂方便的灌注治疗药物。阻断Sxc-/GPx4/ROS信号通路可诱发铁死亡，高效抑制膀胱癌细胞增殖。本课题组前期研究表明索拉非尼可抑制铁死亡上游靶点胱氨酸/谷氨酸反向转运体（Sxc-）的表达，但是下游信号通路规避了其调控，造成铁死亡逃逸；谷胱甘肽过氧化物酶4（GPx4）抑制剂FIN56对上游无调控作用。本项目拟针对Sxc-/GPx4/ROS信号通路，以FIN56和索拉非尼为先导化合物，拼合其分子结构中药效团芴酮肟基和脲基，并在末端连接具有良好水溶性的柔性链，设计合成三个系列芴酮肟基-双芳基（硫）脲衍生物。项目将在细胞、分子、基因和整体动物多个水平考察所合成化合物抗膀胱癌的活性，深入研究其诱导铁死亡和抑制增殖的功能；探讨其作用机制及构效关系。经过活性筛选，以期获得1–2个可高效抑制膀胱癌细胞增殖，毒性低，适宜灌注的候选化合物。

In the treatment of bladder cancer, the efficacy of pirarubicin is not satisfactory; many other chemotherapeutic agents are not suitable for intravesical instillation due to their very low water solubility. Therefore, it is urgent to develop those agents for perfusion which can effectively kill bladder cancer cells with low toxicity. Blocking the Sxc-/GPx4/ROS signaling pathway can induce ferroptosis and effectively inhibit the proliferation of bladder cancer cells. In our previous study, it was found that sorafenib could suppress the expression of ferroptosis upstream target—cystine/glutamate antiporter (System xc-, Sxc-), but it was unable to block downstream signal transduction, which caused the failure of ferroptosis regulation; while glutathione peroxidase 4 (GPx4) inhibitor FIN56 had no effect on the upstream targets. Based on these results and bioisosterism strategy, in this project two pharmacophores of sorafenib and FIN56—ureido and fluorenonyloximido moieties are organically combined, and a flexible chain with high water solubility is linked at the far end; then three series of fluorenonyloximido bisaryl(thio)urea derivatives are designed and synthesized. Their antiproliferative effects and function in mediating ferroptosis will be evaluated at multiple levels (cellular, molecular, genetic, and animal), the molecular mechanisms of anti-bladder cancer and structure-activity relationships will be elucidated. Finally, 1–2 candidates with high efficacy in inhibiting bladder cancer cell proliferation, low side effects, and suitable for intravesical instillation will be obtained.