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

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 cytotoxicity and confirm the intimate structure-activity relationship (SAR) and the anticancer mechanism.

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。

本项目以蒽酮L-鼠李糖苷prinoidin及L-鼠李糖糖脂mezzettiaside-6等为苗头化合物，基于生物电子等排体原理等药物设计的基本方法，设计合成了3 个系列的氧杂蒽酮糖缀合物。所合成的目标化合物的化学结构均经NMR、HREMSI、IR等确认。在此基础上，测试了所合成的目标化合物体外对几种肿瘤细胞株的细胞毒活性和对拓扑异构酶Topo的抑制活性。活性结果显示，在氧杂蒽酮的C-1位引入含氮侧链或在氧杂蒽酮的C-1与C-8位并入咪唑环有助于增加其细胞毒活性。在氧杂蒽酮及其衍生物的C-3位酚羟基引入2,3-二-乙酰基-L-鼠李糖链可显著提高其抗肿瘤活性。进一步的分子生物学机理研究表明：该类糖基修饰的氧杂蒽酮衍生物对KB细胞具有明显的G2/M期阻滞作用，内源性通路及外源性通路均参与了该类合物的细胞凋亡诱导作用。研究证明该类化合物可以剂量依赖性地抑制Topo I介导的pBR322解旋反应并能够抑制TopoII介导的kDNA去连环作用。. 此外，基于分子对接及生物电子等排体原理等实现骨架跃迁，用四氢异喹啉、五环三萜等骨架替换氧杂蒽酮母体设计合成了三个系列的目标化合物。嘧啶基（硫代）氨基脲衍生物对几种肿瘤细胞株及耐药细胞株均具有较强的细胞毒作用。四氢异喹啉衍生物对多种肿瘤细胞株具有较强的细胞毒作用并能够抑制磷酸二酯酶4。以马铃薯三糖薯蓣皂苷YC-72为苗头化合物，设计合成了系列马铃薯三糖五环三萜并测试了其对H5N1假流感病毒的抑制作用，初步阐明了该类化合物的构效关系及作用机制。马铃薯三糖五环三萜作为新型的TopoII抑制剂，体外对多种肿瘤细胞株均具有较强的抑制作用。