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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。
To study the inhibitory effect of coumarin derivatives on human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT), protease (HIV-1 PR) and intracellular replication and their structure-activity relationship. Different coumarin derivatives have been shown to inhibit HIV-1 RT, HIV-1 PR activity and have shown to inhibit HIV-1 replication in the cell. According to the characteristics of domestic traditional pharmacy, this research investigated the tetracyclic bispyridium coumarins and their analogs, which were designed and synthesized with natural products as the lead compound and HIV-1 protease three-dimensional structure. HIV-1 RT and HIV-1 PR and intracellular viral replication as the target, the use of enzymatic and cell culture models for drug screening and structure-activity relationship studies, the design of the seven compounds synthesized pharmacodynamics experimental results show , Some of the compounds showed varying degrees of anti-HIV-1 activity. Among them, V0201 had the strongest effect, and its IC50 of HIV-1 PR and HIV-1 RT were 3.56 and 0.78μmol.L-1, respectively. The IC50 of V0201 in HIV-1 replication was 0.036μmol.L- 1. These results show that compound V0201 has a completely new structure and may become the new lead compound.