苦参酸衍生物的合成及抗丙型肝炎病毒活性研究

自主创新的12-N-对甲氧苄基苦参酸(1)是一个全新结构骨架的抗丙型肝炎病毒(HCV)化合物,主要通过下调宿主肝细胞热休克应急蛋白70(Hsc70)的基因表达而发挥抗HCV活性。本研究以化合物1为先导化合物,合成与评价一系列新苦参酸衍生物的抗HCV活性,进一步完善此类化合物的抗HCV构效关系,同时通过安全性与药代动力学等初步成药性评价,获得具有较高成药性的抗HCV化合物,为将此类化合物发展成一类新型抗HCV药物奠定基础。共设计合成了15个全新结构的苦参酸衍生物,采用qRT-PCR方法测定它们对HCV感染复制的抑制作用,通过药代动力学和急毒试验评价了代表性化合物12-N-间硝基苄基苦参酸(5b)的成药性特征。12-N上的苄基片段为活性必需基团。化合物5b具有较好的抗HCV活性,选择性指数(SI)高于38。另外5b还显示出良好的药代动力学特征和安全性(LD501 000mg/kg)。化合物5b表现出较高的成药性特征,值得进一步研究。

Synthesis and biological evaluation of matrinic acid derivatives as anti-hepatitis C virus agents

Our innovative 12-N-p-methoxymatrinic acid （1） is a promising anti- hepatitis C virus （HCV） agent bearing a novel structure skeleton, and its mechanism is to down-regulate host heat-stress cognate 70 （Hsc70） gene expression. Taking compound 1 as the lead, a series of novel matrinic acid derivatives were synthesized and evaluated for their anti-HCV activity to fur ther replenish the anti HCV structure-activity relationship （SAR） of these compounds. Novel anti-HCV candidate（s） character- ized by a high druggability would be screened out by a comprehensive evaluation on safety and pharmacokinetic properties, thus to lay a foundation for the development of such compounds to be a class of novel anti-HCV drugs. Totally 15 novel target com- pounds have been designed and synthesized. Their inhibition towards HCV replication was tested by qRT-PCR, and the drugga- bility of a representative compound 12-N-m-nitrobenzyl matrinic acid （5b） was evaluated by pharmacokinetic and acute toxicity tests. SAR result disclosed that the benzyl fragment was beneficial for the activity. Compound 5b displayed good anti-HCV activ- ity, with an SI index higher than 38. Furthermore, it showed a good pharmacokinetic profile as well as a high safety （LDs0 ~〉 1 000 mg/kg） in vivo by oral administration, indicating a druggable nature of the structure. Therefore, we consider that compound 5b is promising for further study.