CCR5和CXCR4双重抑制剂的设计、合成及活性评价

发布时间：2018-04-15 04:10

本文选题：艾滋病 + 抑制剂　；参考：《湘潭大学》2014年硕士论文

【摘要】：艾滋病（AIDS）全称为获得性免疫缺陷综合症，是由人类感染免疫缺陷病毒HIV引起的疾病，严重危害着人类的健康和社会经济的发展。HIV病毒侵入靶细胞需要辅助受体CCR5或CXCR4的协助，抑制HIV病毒与CCR5或CXCR4的结合作用可以有效抑制HIV病毒感染靶细胞。近年来，以CCR5为靶标的辅助受体抑制剂受到了多个跨国制药公司和学术机构的关注与研究，已发现了许多CCR5小分子抑制剂，已有一个CCR5抑制剂于2007年上市（辉瑞公司的马拉维诺）。相比CCR5抑制剂，CXCR4类小分子抑制剂研究较少，目前已发现的结构为双环拉胺类、四氢喹啉苯并咪唑多胺类与胍类抑制剂具有很强的抗HIV活性。然而，单独使用CCR5或CXCR4抑制剂具有局限性，如单一的辅助受体抑制剂只对各自特异的病毒有效且使用CCR5抑制剂前需要进行病毒检测，患者长期应用CCR5抑制剂可导致HIV病毒变异与CXCR4结合进入靶细胞等。本论文在实验室前期合成的部分3-甲基吡啶苄基多胺类化合物与四氢喹啉-苯并咪唑多胺类化合物的基础上，再结合CCR5和CXCR4受体的结构信息及构效关系的分析，运用药效团拼接，官能团位置转变或变化等经典药物设计方法，设计并合成了一系列新的四氢喹啉苄基多胺类抑制剂，并测定了其抗HIV-1CXCR4病毒株的活性。具体工作主要包括： 1．以AnorMED公司研究的AMD070为模板，设计并合成了10个四氢喹啉-苄基氨基多胺类化合物。 2．设计合成了5个四氢喹啉-苄基胍基多胺类化合物。 3．设计合成了5个四氢喹啉-哌啶甲酰胺类化合物。 4．本论文所合成得3个系列，共20个全新的目标化合物，，结构经质谱（MS）、核磁共振（1H-NMR）确证，SciFinder检索证实为新化合物。 5．活性测定结果表明：四氢喹啉-苯并咪唑多胺类化合物具有较好的抗HIV活性（IC50＜1μmol/L），四氢喹啉-苄基多胺类化合物活性较差（IC50＞8μmol/L）。目前所得构效关系可为新一轮的抗CCR5及CXCR4双功能抑制剂优化提供借鉴。
[Abstract]:AIDS AIDS AIDS AIDSis a disease caused by human immunodeficiency virus (HIV), which is a disease caused by human immunodeficiency virus (HIV). It is a serious threat to human health and social and economic development. HIV invades target cells with the assistance of CCR5 or CXCR4.Inhibiting the binding of HIV virus to CCR5 or CXCR4 can effectively inhibit the infection of HIV virus in target cells.In recent years, the coreceptor inhibitors targeting CCR5 have attracted the attention and research of many multinational pharmaceutical companies and academic institutions, and many small molecular inhibitors of CCR5 have been found.A CCR5 inhibitor has been listed in 2007 (Pfizer's Malawi Northrop.Compared with CCR5 inhibitor CXCR4 small molecular inhibitors have been found to be bicyclic amines tetrahydroquinoline benzimidazole polyamines and guanidine inhibitors have strong anti- activity.However, the use of CCR5 or CXCR4 inhibitors alone has limitations, such as the fact that a single coreceptor inhibitor is only effective against specific viruses and that virus testing is required before the use of CCR5 inhibitors.Long-term use of CCR5 inhibitors can lead to HIV virus mutation and CXCR4 binding into target cells, etc.Based on the partial synthesis of 3-methylpyridine benzyl polyamines and tetrahydroquinoline-benzimidazolium polyamines, the structural information and structure-activity relationship of CCR5 and CXCR4 receptors were analyzed.A series of novel tetrahydroquinoline benzyl polyamines inhibitors were designed and synthesized by classical drug design methods, such as pharmacophore splicing, functional group position transition or change, and their activity against HIV-1CXCR4 virus strain was determined.Specific efforts include, inter alia:1.Ten tetrahydroquinoline-benzyl amino polyamines were designed and synthesized from AMD070 prepared by AnorMED.2.Five tetrahydroquinoline benzyl guanidine polyamines were designed and synthesized.3.Five tetrahydroquinoline-piperidinamide compounds were designed and synthesized.4.Three series of new target compounds were synthesized in this paper. The structures were confirmed to be new compounds by MS MS NMR 1H-NMRs.5.The results showed that tetrahydroquinoline-benzimidazole polyamines had better anti- activity (IC50 < 1 渭 mol / L), and tetrahydroquinoline benzyl polyamines had lower activity than 8 渭 mol 路L ~ (-1) 路L ~ (-1) 路L ~ (-1) 路L ~ (-1) 路L ~ (-1) 路L ~ (-1) 路L ~ (-1) 路L ~ (-1).At present, the structure-activity relationship can be used as a reference for the optimization of anti-CCR5 and CXCR4 bifunctional inhibitors.
【学位授予单位】：湘潭大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914;O626

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