NOVEL HETEROCYCLIC ANTI HIV AGENTS

新型杂环抗艾滋病毒药物

• 批准号: 3769154
• 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/3769154
• 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-甲基哌嗪基）-4，5-二氢噻吩并[2，3-c]吖啶（LS-342）是 在PBM和Vero细胞中基本无毒，浓度大于 在感染的人PBM细胞中具有抗HIV-1活性 与浓度为2微摩尔的HIV-1（LAV-1株）。 几 LS-342的未稠合类似物在1微摩尔 浓度水平。 基于初步的QSAR分析，DNA结合 研究，RNA结合研究，尝试 用活性化合物抑制病毒RT和蛋白酶， 工作假设已经形成， 活性杂环芳烃 这类化合物与病毒RNA相互作用。 更具体地说， 拟议的研究是基于工作假设， 活性化合物识别基因中RNA的特定构象， HIV-1基因组的控制区，由于存在不寻常的 结构特征，如基部凸起或基部环。 一个理性 提出了一种新的抗HIV-1杂环芳烃的方法 高活性试剂（与病毒RNA的强特异性结合） 和低细胞毒性（与宿主DNA的结合可忽略不计）。 这个问题 将通过设计具有结构特征的分子， 可以增加这些分子与RNA的结合 和/或 减少与DNA的结合。 杂多芳族分子 建议开发的抗HIV-1药物本质上含有 扭曲的、稠合的环系统或未稠合的环系统，其可以获得 扭曲构象 分子扭曲并不能阻止复杂的 形成具有碱基凸起或环状的分子 上的区域 RNA，但强烈阻碍与DNA形成稳定的复合物。 阴离子或潜在的阴离子取代基将连接到 这些分子的杂芳族系统。 这些取代基，当 正确定位，强烈稳定与RNA的复合物，但在 一般来说，使取代的分子与 DNA. 分子还将含有阳离子基团，其稳定 与核酸的相互作用。 适当的手性将是 在这些基团处引入以阻止与DNA形成复合物。 的 芳香族分子中的偶极矩取向的规则， 它们与核酸的相互作用，最近在这方面发展起来， 实验室，也将帮助这项研究。 最后，双功能 分子，RASORS，将与项目合作合成 3. RASORS对病毒RNA具有高度特异性。 设计和 合成工作将以QSAR分析为指导。