以HDACs为靶标的抗肿瘤先导化合物ZYJ-34c的成药性研究

项目名称： 以HDACs为靶标的抗肿瘤先导化合物ZYJ-34c的成药性研究

项目编号： No.21302111

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 张颖杰

作者单位： 山东大学

项目金额： 25万元

中文摘要： 在众多与表观遗传修饰相关的酶系中，组蛋白去乙酰化酶（HDACs）与肿瘤关系的研究较为透彻，已成为抗肿瘤药物设计的热门靶标。本课题前期工作设计合成了一系列四氢异喹啉类HDACs抑制剂，其中化合物ZYJ-34c具有比已上市的HDACs抑制剂SAHA更强的抗肿瘤活性，已作为抗肿瘤先导化合物进入临床前研究开发阶段。然而初步的稳定性和药代动力学结果表明，ZYJ-34c的血浆稳定性差且口服生物利用度低。因此，本课题拟主要围绕以下两方面展开研究：1. 针对ZYJ-34c的药代动力学缺陷对其进一步结构改造和优化，以提高其生物利用度和代谢稳定性；2. 寻找可能存在的ZYJ-34c体内活性代谢产物，并对其进行化学合成、结构鉴定和成药性评价。这两方面工作都有利于找到新的高效、低毒、具有良好药代动力学特征的抗肿瘤先导化合物，为开发具有我国自主知识产权的HDACs抑制剂类抗肿瘤药物奠定基础。

中文关键词： 组蛋白去乙酰化酶；抑制剂；抗肿瘤；；

英文摘要： Among the epigenetic enzymes, histone deacetylases (HDACs) have now emerged as a promising class of antitumor targets due to their close relationship with tumor. In our previous research, a novel series of tetrahydroisoquinoline-based HDACs inhibitors were designed and synthesized, among which ZYJ-34c exhibited higher antitumor activity than the approved HDACs inhibitor SAHA and entered preclinical research as lead compound. However, preliminary stability study and pharmacokinetic study of ZYJ-34c revealed that its plasma stability and oral bioavailability were poor. Therefore, our subsequent research mainly focused on the following two aspects: 1. Further structure modification and optimization of ZYJ-34c to improve its oral bioavailability and plasma stability. 2. Total synthesis, structure confirmation and drug-like property evaluation of the possible in vivo metabolites of ZYJ-34c; Aforementioned related research might lead to more promising antitumor lead compounds with better pharmacokinetic profiles and lay a solid foundation for the research and development of HDACs inhibitors as antitumor drugs with our own intellectual property.

英文关键词： histone deacetylase；inhibitor；antitumor；；