新型靶向肿瘤细胞活性氧可诱导DNA交联剂的合成及分子作用机制研究

项目名称： 新型靶向肿瘤细胞活性氧可诱导DNA交联剂的合成及分子作用机制研究

项目编号： No.21202022

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 有机化学

项目作者： 匡云艳

作者单位： 复旦大学

项目金额： 25万元

中文摘要： 在前期创新性研究工作（Yunyan Kuang, et al. J. Am. Chem. Soc., 2011, 133, 19278-19281）的基础上，本项目将靶向肿瘤细胞高含量活性氧（reactive oxygen species, ROS）标志物，设计并合成一系列由"ROS受体激发单元（trigger）+DNA毒性单元（effector）"构成的可诱导DNA交联剂，该类分子到达靶目标后，通过激活引发单元的反应来促使分子释放活性体片段（effector 1）以及产生新的细胞毒性单元（effector 2，双醌甲基分子biquinone methides）协同阻断DNA复制而造成细胞凋亡。通过DNA交联（或烷基化）反应以及体外细胞活性筛选来评价化合物的生物活性。新的靶向目标药物分子将通过改变细胞内ROS的含量、释放多个DNA交联剂的双重作用模式高效抑制肿瘤的转移和侵袭。

中文关键词： DNA交联剂；活性氧；乏氧；抗肿瘤；抗炎

英文摘要： Based on our preliminary data (Yunyan Kuang, et al. J. Am. Chem. Soc., 2011, 133, 19278-19281), a class of novel ROS inducible DNA cross-linking agents will be designed, synthesized and characterized, which are targeting the increased intrinsic ROS stress in cancer cells. Such agents consist of two separate functional domains: a ROS-accepting moiety ('trigger') and a DNA damage moiety ('effector'). They are expected to release pharmacologically active species and generate biquinone methide as additional potent effector to disrupt DNA replication and transcription upon activation by ROS. The selectivity and activity of these novel prodrugs toward ROS was determined by measuring DNA interstrand cross-links and/or DNA alkylation and the cytotoxicity against the cancer cell lines and non-cancer cell lines. The ideal ROS-targeting agents should have a dual mode of action: reducing the amount of ROS available to induce cancer, while also generating toxic species in cancer cell.

英文关键词： DNA cross-linking agents；reactive oxygen species；hypoxia；anti-tumor；anti-inflammatory