谷胱甘肽S转移酶（GST）靶向的新型NO供体型抗肿瘤药物的设计、合成和生物活性研究

项目名称： 谷胱甘肽S转移酶（GST）靶向的新型NO供体型抗肿瘤药物的设计、合成和生物活性研究

项目编号： No.81202408

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 黄张建

作者单位： 中国药科大学

项目金额： 24万元

中文摘要： 谷胱甘肽S转移酶（GST）P亚型之所以作为一个有前景的抗肿瘤药物的靶点，是因为其在多数肿瘤细胞表面过度表达，且与肿瘤细胞的耐药性密切相关。我们发现，O2-磺酰基乙基偶氮鎓二醇盐可以在碱性条件下或者在碱性氨基酸存在下被活化，发生β-消除反应后，生成偶氮鎓二醇盐片段，进而释放NO。进一步研究表明，GST P酶也可以活化O2-磺酰基乙基偶氮鎓二醇盐衍生物，发生β-消除反应，进而释放NO。基于上述研究，本项目设计、合成O2-磺酰基乙基偶氮鎓二醇盐修饰的谷胱甘肽类似物，前期的计算机模拟及体外活性测试结果已表明，目标化合物作为GST P酶的底物，能特异性地被其活化，并显示了强效的体外抗肿瘤活性。在此基础上，拟进一步优化化合物结构，以提高GST P亚型的选择性和抗肿瘤活性，并进行定性、定量构效关系研究，体内、外抗肿瘤活性及其作用机制研究，为最终获得 GST P靶向的新型NO供体型抗肿瘤药物奠定坚实基础。

中文关键词： 谷胱甘肽S转移酶；NO供体；beta-消除反应；抗肿瘤；靶向性

英文摘要： Overexpression of glutathione S-transferase (GST) P isozyme in many tumor cells was considered as a possible mechanism of tumor cell drug resistance. In this regard, GST P is emerging as a promising target for managing the development of anticancer agents. Previous research project involved the synthesis of a new series O2-sulfonylethyl protected diazen-1-ium-1,2-diolate compounds. This new series of O2- sulfonylethyl diazeniumdiolate compounds could release NO in a non-physiological alkaline buffer, or in the presence of bases such as the basic natural amino acids Arg and His in PBS at pH 7.4, via a β-elimination cleavage reaction. Further study revealed that that GST P can also active O2-protected compounds to release NO via the same β-elimination pathway. Based on these findings, the concept of O2-sulfonylethyl diazeniumdiolate-based glutathione derivatives was proposed in this project. The preliminary modeling study and in vitro anti-cancer assessment showed that the target compounds which have been successfully synthesized can be activated by GST P and show potent inhibitory activities against cancer cells growth in vitro. The further works include: 1) modifying GSH moiety and diazeniumdiolate secondary amine moiety to improve the selectivity for GST P isozyme and enhance anti-cancer activities; 2) quantita

英文关键词： GGlutathione S-transferase；NO donors；beta-elimination reaction；anti-cancer；targeting