铜介导的促氧化抗癌分子设计及其机制研究

Increased levels of reactive oxygen species (ROS) and redox copper observed in cancer cells compared with normal cells could be exploited for developing anticancer agents by designing copper-mediated prooxidants. In this project, we will select catechol-type resveratrol analogs and enediolic ascorbic acid to probe whether they make use of endogenous copper ions to construct an efficient prooxidant system which contributes to their cancer chemopreventive and chemotherapeutic activity including cytoprotective effects against oxidative injury by activating the Keap1-Nrf2/ARE pathway, anti-inflammatory effects, activities in inducing cell cycle arrest, apoptotic and autophagic cell death of cancer cells, activity in reversing the chemoresistance of cancer cells against conventional anticancer agents by targeting glutathione S-transferases, and anti-metastatic efficacy. We believe that the research may have broad chemical and biological implications for elucidating the importance of the catechol and enediolic moieties in cancer chemoprevention, understanding why dietary natural products with these moieties tend to show cancer chemopreventive activity. On this basis, we will design a series of natural products-inspired Cu(II) reactors and ionophores as well as Cu(II) pro-reactors and pro-ionophores based on the strategy of hydrogen peroxide- or glutathione-responsive drug release. The emphasis will be given especially on clarifying their structural basis and chemical driving forces as Cu(II) reactors and ionophores as well as the mechanisms underlying their anticancer activity. These studies will give us useful information for designing copper-dependent prooxidative anticancer agents.

癌细胞与正常细胞相比具有提高水平的活性氧和氧化还原活跃的铜，因此设计铜介导的促氧化剂可能是发展抗癌试剂的重要策略。本项目以具有邻苯二酚结构单元的白藜芦醇类似物和具有烯二醇结构单元的维生素C作为分子探针，研究它们是否利用胞内铜离子构建促氧化体系在癌预防和治疗的各个阶段（包括：激活Keap1-Nrf2/ARE信号通路实现细胞氧化性损伤保护、抑制炎症发生、诱导癌细胞周期受阻、凋亡或自噬性死亡、抑制谷胱甘肽S转移酶实现耐药癌细胞的敏化和抑制癌细胞转移）实施其抗癌活性。试图从促氧化的癌预防和治疗角度诠释邻苯二酚和烯二醇结构单元的重要性。在此基础上，设计天然产物导向的Cu(II)反应体和Cu(II)载体并利用癌细胞的氧化还原特征设计前Cu(II)反应体和前Cu(II)载体，研究它们作为Cu(II)反应体和Cu(II)载体的结构基础、化学驱动力和抗癌活性机制，并提供设计铜介导的促氧化抗癌试剂的相关信息。

本项目以天然产物分子为先导，设计了铜介导的促氧化抗癌分子，探究了它们作为铜反应体和铜载体的结构基础、化学驱动力以及选择性杀死癌细胞的活性机制，为进一步精准设计天然产物导向的促氧化抗癌药物提供通用策略。主要研究结果包括：（1）以邻苯二酚型二苯多烯作为邻苯二酚型饮食类多酚的模型，发现：它们能够利用癌细胞内高水平的铜离子构建促氧化体系，产生活性氧，进而干预癌的引发、促进和发展。阐明了邻苯二酚型分子在癌细胞内作为铜反应体的角色，并系统性地证实铜介导的促氧化机制在干预癌进程各个阶段的普适性。（2）基于邻苯二酚结构设计并发现了具有前景的铜反应体型促氧化抗癌先导。如：设计邻苯二酚型二苯丁二烯作为促氧化抗黑色素瘤分子，它通过构建氧化还原循环靶向黑色素瘤细胞多个氧化还原特征，实现高选择性杀死黑色素瘤细胞；设计GSH激活的前邻苯二酚型二苯己三烯作为促氧化抗癌诊疗前药，实现药物释放、定位和活性的可视化。（3）阐明了酮-烯醇式结构单元在设计铜载体中的重要性。（4）基于酮-烯醇式结构设计并发现了具有前景的铜载型促氧化抗癌先导。如GSH激活的前铜载体PHF和H2O2激活的前铜载体PNaP，实现以“一石多鸟”的方式靶向癌细胞多个氧化还原特征进而高选择性杀死癌细胞。