中文摘要
本项目基于核苷类抗病毒药物构效关系研究，根据生物电子等排的原理，将具有高活性、低毒性的L-核苷和氮杂糖结构特征结合起来，设计合成核苷及类核苷等糖类衍生物，以期发新型高效低毒抗病毒药物提供先导化合物。以天然单糖为起始原料，设计合成了多个系列新的双环氮杂糖衍生物、螺噁嗪烷酮类核苷衍生物、二聚核苷、双碱基类核苷衍生物以及新型噻唑烷酮非核苷-核苷类抗病毒衍生物等；利用Staudinger/Aza-Wittig/缩合反应以及Staudinger/Aza-Wittig/还原反应，一锅法分别简便合成了噻唑烷酮基类核苷衍生物、噻唑烷酮连接双糖、以及氨基连接双糖和5'-N-芳基类核苷等衍生物；系统研究了微波促进反应在糖类衍生物合成中的应用。分别测定并比较了所合成化合物对糖苷酶、HIV逆转录酶、HCMV、VZV、肿瘤细胞、植物病菌等的抑制活性，初步发现糖基噻唑烷酮衍生物、噻唑烷酮非核苷-核苷类抗病毒衍生物和含芳基类核苷衍生物具有良好的抗病毒活性；二聚核苷、双碱基类核苷衍生物未表现出对HIV逆转录酶的抑制作用，但有明显的抗肿瘤作用。以上研究结果为进一步设计合成糖类及核苷类抗病毒、抗肿瘤药物奠定了基础。
英文摘要
On the basis of the recent achievements on QSAR of nucleoside antiviral agents, series of new nucleoside mimetics and analoges containing azasugar and some heterocyclic base moieties have been designed and synthesized for discovering highly active and low toxic Anti-HIV and Anti-HBV agents using natural monosugars as the starting materials. Several novel functionalized bicyclic imnosugar derivatives, spiro oxazinanone nucleoside analoges, dinucleoside derivatives, nucleoside analoges with two heterocyclic bases and thioxazoliinone non-nucleoside analoges were effectively synthsized. Series of thioxazoliinone nucleoside analoges, thioxazoliinone linked disaccharides, were conveniently synthesized by tendam Staudinger/Aza-Wittig/ condensation reactions, and novel amine-linked disaccharides and 5'-aryl-N- nucleoside derivatives have been also successifully synthesized by tendam Staudinger/Aza-Wittig/reduction. .The biological activities of the synthesized compounds for anti HIV-RT, anti-HCMV, anti VZV, antitumor and against glycosides were evluated in vitro. The glycosyl thioxazoliinones, thioxazoliinone non-nucleoside analoges, 5'-aryl-N- nucleoside derivatives showed very good antiviral activity, and the dinucleoside derivatives and the nucleoside analoges with two heterocyclic bases showed no antiviral activity, but good antitumor activity, which will be helpful for designing and developing a good effective and low toxic new anti-virus drug.
结题摘要
本项目基于核苷类抗病毒药物构效关系研究，根据生物电子等排的原理，将具有高活性、低毒性的L-核苷和氮杂糖结构特征结合起来，设计合成核苷及类核苷等糖类衍生物，以期发新型高效低毒抗病毒药物提供先导化合物。以天然单糖为起始原料，设计合成了多个系列新的双环氮杂糖衍生物、螺噁嗪烷酮类核苷衍生物、二聚核苷、双碱基类核苷衍生物以及新型噻唑烷酮非核苷-核苷类抗病毒衍生物等；利用Staudinger/Aza-Wittig/缩合反应以及Staudinger/Aza-Wittig/还原反应，一锅法分别简便合成了噻唑烷酮基类核苷衍生物、噻唑烷酮连接双糖、以及氨基连接双糖和5'-N-芳基类核苷等衍生物；系统研究了微波促进反应在糖类衍生物合成中的应用。分别测定并比较了所合成化合物对糖苷酶、HIV逆转录酶、HCMV、VZV、肿瘤细胞、植物病菌等的抑制活性，初步发现糖基噻唑烷酮衍生物、噻唑烷酮非核苷-核苷类抗病毒衍生物和含芳基类核苷衍生物具有良好的抗病毒活性；二聚核苷、双碱基类核苷衍生物未表现出对HIV逆转录酶的抑制作用，但有明显的抗肿瘤作用。以上研究结果为进一步设计合成糖类及核苷类抗病毒、抗肿瘤药物奠定了基础。