基于靶点结构的新型DAPY类HIV-1 NNRTIs的设计、合成及活性研究
详细信息 查看官网全文
- 英文论文题名：Structure-based Design,Synthesis and Biological Evaluation of Novel DAPY Derivatives as HIV-1 NNRTIs
- 论文作者：李潇 ; 展鹏 ; 刘新泳
- 英文论文作者：Xiao Li ; Peng Zhan ; Xinyong Liu ; Department of Medicinal Chemistry ; School of Pharmaceutical Sciences ; Shandong University
- 年：2016
- 作者机构：山东大学药学院药物化学研究所;
- 论文关键词：HIV-1 ; NNRTIs ; DAPY
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第二十八分会：化学生物学
- 语种：中文
- 分类号：TQ460.1
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第二十八分会 ; 化学生物学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：200k
- 原文格式：D
- 会议级别：全国
摘要
二芳基嘧啶(DAPY)类化合物是具有良好抗野生型和多种突变型HIV-1活性的NNRTIs。对该类抑制剂的上市药物TMC125与RT复合物的晶体结构解析发现,其嘧啶环1-位的氮原子位于连续的赖氨酸序列(K101-K104)周围并与之存在较大的空间距离,在该位置引入一些延伸的氢键供体或受体可能与周围的赖氨酸产生额外的氢键作用。基于以上结构信息,我们设计合成了一系列新型DAPY类衍生物,活性最好的LX-1抗野生型HIV-1(ⅢB)的EC_(50)值为2.5 nM,并对K103N/Y181C HIV-1双突变株(RES056)保持中等抑制活性(EC_(50)=0.33μM)。对LX-1进行进一步的结构优化,右臂采用含杂原子的芳环或饱和环系以增加与周围氨基酸的潜在氢键作用,并在末端引入亲水基团以改善分子水溶性。同时对LX-1嘧啶5-位氨基进行多样性修饰以探讨构效关系。活性突出的化合物LX-2保持了LX-1抗野生型HIV-1的活性(EC_(50)=2.6 nM),同时对多种单突变的抑制活性也达到纳摩尔水平,对K103N/Y181C HIV-1双突变株的抑制活性较LX-1有所提高,具有进一步研发的价值。
Guided by crystal structures of HIV-1 RT/DAPY complex,a series of novel DAPY derivatives were rationally designed,in which the positions of nitrogen atom in pyrimidine ring were changed with other nitrogen-containing groups to build potential hydrogen bonds.LX-1 was the most potent compound against WT and K103N/Y181 C HIV-1 with an EC50 value of 2.5 nM and 0.33 μM.Further optimization of LX-1 led to the discovery of compound LX-2,which has a nitrogen-containing heterocycle as right wing.In cell-based anti-HIV-1 assay,it displayed improved activity against a variety of mutant HIV-1 strains compared to LX-1.
Guided by crystal structures of HIV-1 RT/DAPY complex,a series of novel DAPY derivatives were rationally designed,in which the positions of nitrogen atom in pyrimidine ring were changed with other nitrogen-containing groups to build potential hydrogen bonds.LX-1 was the most potent compound against WT and K103N/Y181 C HIV-1 with an EC50 value of 2.5 nM and 0.33 μM.Further optimization of LX-1 led to the discovery of compound LX-2,which has a nitrogen-containing heterocycle as right wing.In cell-based anti-HIV-1 assay,it displayed improved activity against a variety of mutant HIV-1 strains compared to LX-1.
引文
Li,X.;Chen,W.M.;Tian,Y.;Liu,H.Q.;Zhan,P.*;De Clercq,E.;Christophe,P.;Balzarini,J.;Liu,X.Y.*.Eur J Med Chem.2014,80:112.