摘要
研究香豆素衍生物对人类免疫缺陷病毒1型逆转录酶(HIV-1 RT)、蛋白酶(HIV-1 PR)和细胞内复制的抑制作用及其构效关系。不同香豆素衍生物具有抑制HIV-1 RT、HIV-1 PR活性,且在细胞内显示出抑制HIV-1复制的作用已见报道。本课题根据国内传统药学的特点,考察以天然产物为先导化合物、结合HIV-1蛋白酶三维结构计算机辅助药物设计、合成的四环双吡喃香豆素及其类似物。以HIV-1 RT及HIV-1 PR以及细胞内病毒复制为靶点,利用酶学模型和细胞培养模型进行药物筛选及其构效关系研究,设计合成的7个化合物的药效学实验结果显示,部分化合物显示了不同程度的抗HIV-1活性。其中V0201作用最强,它对HIV-1 PR和HIV-1 RT的IC50分别为3.56和0.78μmol.L-1;在PBMC培养实验中,V0201对HIV-1复制的IC50为0.036μmol.L-1。这些结果表明,化合物V0201具有全新结构,可能成为新的先导化合物。
The purpose of this study is to find out anti-HIV-1 reverse transcriptase（RT）/protease（PR） activity and inhibition of virus replication in cell cultures of novel coumarin analogs and determine their structure-activity relationship.Coumarin derivatives have been demonstrated to inhibit the activity of HIV-1 RT/PR in cell free system.It also shows inhibition effects to HIV-1 replication in cell culture.Based on the Chinese traditional pharmacological characteristics and protein three dimension computer aided design,analogs of tetracyclic dipyranocoumarin were synthesized from natural leading compounds.We studied the relationship of antiviral effects and chemical structures via HIV-1 PR/RT enzyme models and cell culture model system.Seven compounds were designed and tested.Several compounds showed anti-HIV-1 activity in varying degrees,especially V0201 showed much higher anti-HIV-1 activity with 3.56 and 0.78 μmol·L-1 of IC50 against HIV-1 PR/RT and 0.036 μmol·L-1 against HIV-1 replication in PBMC cultures.V0201 with a novel structure may be a new leading compound.These new compounds are valuable for development of new anti-HIV drugs in the future.
出处
《药学学报》
CAS
CSCD
北大核心
2011年第1期35-38,共4页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(39970868)
