NOVEL HETEROCYCLIC ANTI HIV AGENTS

新型杂环抗艾滋病毒药物

• 批准号: 3803759
• 负责人: LUCJAN STREKOWSKI
• 金额: --
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3803759
• 关键词: aminoacridines; antiAIDS agent; antiviral agents; chemical stability; chemical structure function; conformation; cooperative study; drug design /synthesis /production; heterocyclic polycyclic compound; high performance liquid chromatography; human immunodeficiency virus 1; molecular polarity; molecular site; nucleic acid structure; nucleobase; pyridine; quinazolines; quinoline analog; stereoisomer; virus RNA

6-(4-Methylpiperazino)-4,5-dihydrothieno[2,3-c]acridine (LS-342) is essentially non-toxic in PBM and Vero cells at concentrations greater than 100 micromoles and active against HIV-1 in human PBM cells infected with HIV-1 (strain LAV-1) at the concentration of 2 micromoles. Several unfused analogs of LS-342 are also active at the 1 micromole concentration level. Based on the preliminary QSAR analysis, DNA binding studies, RNA binding studies, negative results of the attempted inhibition at both viral RT and protease with the active compounds, a working hypothesis has been formulated that active heteropolyaromatic compounds of this class interact with the viral RNA. More specifically, the proposed research is based on the working hypothesis that the active compounds recognize a specific conformation of the RNA in gene control region of the HIV-1 genome due to the presence of unusual structural features such as base bulges or loops of bases. A rational approach is proposed to developing novel heteropolyaromatic anti-HIV-1 agents of high activity (strong and specific binding to the viral RNA) and low cell toxicity (negligible binding to host DNA). This problem will be attacked by designing molecules with the structural features that are known to increase binding of these molecules with RNA and/or decrease their binding with DNA. The heteropolyaromatic molecules proposed for the development as anti-HIV-1 agents contain intrinsically twisted, fused ring systems or unfused ring systems that can attain the twisted conformation. The molecular twist does not prevent complex formation of the molecule with bulges or loops of base regions on the RNA but strongly discourages the formation of a stable complex with DNA. Anionic or potentially anionic substitutent will be attached to the heteroaromatic systems of these molecules. Such substituents, when properly positioned, strongly stabilize the complex with RNA but, in general, destabilize the interaction of the substituted molecules with DNA. The molecules will also contain cationic groups which stabilize the interaction with nucleic acids. A proper chirality will be introduced at these groups to discourage complex formation with DNA. The rules of the dipole moment orientation in the aromatic molecules for their interaction with nucleic acids, recently developed in this laboratory, will also aid in this research. Finally, bifunctional molecules, RASORS, will be synthesized in collaboration with Project 3. RASORS will be highly specific for the viral RNA. The design and synthesis work will be guided by QSAR analyses.

6-(4-Methylpiperazino)-4，5-dihydrothieno[2，3-c]acridine(LS-342)是 在较高浓度下对PBM和Vero细胞基本无毒 感染的人外周血巨噬细胞对HIV-1具有100多微摩尔的活性 与HIV-1(LAV-1株)在2微摩尔浓度下进行免疫反应。几个 LS-342的未融合类似物在1微摩尔也是活性的 浓度水平。根据初步的QSAR分析，DNA结合 研究，RNA结合研究，尝试的阴性结果 活性化合物a对病毒逆转录酶和蛋白酶的抑制作用 已经提出了工作假说，即活性杂多酸 这类化合物与病毒RNA相互作用。更确切地说， 这项拟议的研究是基于这样一个工作假设： 活性化合物识别基因中RNA的特定构象 由于存在异常的HIV-1基因组控制区 结构特征，如底座凸起或底座环状。理性的人 提出了开发新型杂多酸抗HIV-1的途径 高活性试剂(与病毒核糖核酸强而特异的结合) 低细胞毒性(与宿主DNA的结合可以忽略不计)。这个问题 将通过设计具有结构特征的分子来攻击 已知可增加这些分子与RNA和/或 减少它们与DNA的结合。杂多酸分子 建议作为开发中的抗HIV-1药物固有地含有 扭曲的、熔合的环路系统或未熔断的环路系统 扭曲的构象。分子扭曲并不能阻止复合体 形成具有凸起或环的碱基区的分子 RNA，但强烈阻碍与DNA形成稳定的复合体。 阴离子或潜在的阴离子取代基将附着在 这些分子的杂芳烃体系。这样的取代基，当 定位正确，与RNA形成强有力的稳定的复合体，但在 一般情况下，破坏取代分子与 DNA分子还将包含稳定的阳离子基团 与核酸的相互作用。一个适当的手性将是 在这些组织引入，以阻止与DNA形成复杂的结构。这个 芳香族分子偶极矩取向规律的研究 它们与核酸的相互作用，最近在这方面得到了发展 实验室，也将协助这项研究。最后，两种功能 RASORS分子将与Project合作合成 3.RASORS对病毒RNA具有高度特异性。设计和实现了 合成工作将以QSAR分析为指导。