以 TopoIIα为靶点的系列新型氧杂蒽酮衍生物的合成及构效关系研究

项目名称： 以 TopoIIα为靶点的系列新型氧杂蒽酮衍生物的合成及构效关系研究

项目编号： No.21202047

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： 宋高鹏

作者单位： 华南农业大学

项目金额： 25万元

中文摘要： 恶性肿瘤已成为世界范围内严重威胁人类生命的主要疾病之一。蒽环糖缀合物是一类典型的TopoII抑制剂，可作为开发新型抗肿瘤药物的候选化合物。我们在前期研究中以天然产物prinoidin(1)为苗头化合物设计合成了系列蒽环L-鼠李糖苷，进行了体外细胞毒活性研究，建立了初步的构效关系并阐明了其抗肿瘤作用机制。为降低prinoidin的毒性得到更加高效、低毒的新型TopoII抑制剂，我们利用生物电子等排体原理设计合成了系列氧杂蒽酮L-鼠李糖苷及其衍生物。研究表明所合成的吡唑并氧杂蒽酮L-鼠李糖苷(4)可以抑制TopoIIα介导的kDNA去连环作用，其对多种肿瘤细胞株均表现出较强的细胞毒活性而对人正常细胞没有表现出明显的毒性。本研究课题将以此为基础，通过建立药学团模型进一步设计合成系列新的吡唑并氧杂蒽酮衍生物，筛选得到特异性更高、细胞毒活性更强的先导化合物，并确立其详细的构效关系及抗肿瘤作用机制。

中文关键词： 氧杂蒽酮衍生物；糖基修饰；合成；构效关系；TopoII抑制剂

英文摘要： Cancer has been one of the world's most devastating diseases. Anthracene glucosides as new potential anticancer agents could inhibit the catalytic activity of TopoIIα. In our previous work, a series of anthracene L- rhamnopyranosides were designed and synthesized with the natural product prinoidin (1) as the hit compound, of which the cytotoxicities in vitro were evaluated and the preliminary structure-activity relationship (SAR) and the anticancer mechanism were confirmed. A series of novel xanthone L-rhamnopyranosides were designed and synthesized based on the bioisostere principle in order to reduce the toxicity of prinoidin to discover the new lead compound with the stronger cytotoxicity and the weaker toxicity. It was proved that the pyrazole-fused xanthone L-rhamnopyranoside (4) could inhibit the catalytic activity of TopoIIα and showed good cytotoxicities against several human cancer cell lines in vitro without the obvious cytotoxicity against human normal cell line. Based on the above resulats, this research work established the pharmacophore model and will continue to design and synthesize the new pyrazole-fused xanthone derivetives and evaluate their cytotoxicities against several human cancer cell lines in vitro in order to get the new lead compound with the higher selectivity and the stronger cytotox

英文关键词： xanthone derivatives；glycosyl modification；synthesis；structure-activity relationships；TopoII inhibitors