POTENTIAL SYNERGISTIC INHIBITORS OF HIV INFECTIVITY

这项研究计划的长期目标是为人类的发展做出贡献。 发现新一代核苷和杂环系统， 对HIV-1、HIV-2和 耐药的艾滋病毒变种。 这项建议的具体目标是： 新化合物的合成和抗HIV研究， 作为HIV生命周期两个阶段的抑制剂， 包括逆转录（HIV RT抑制剂）和后期阶段 涉及转录HIV基因表达（达特抑制剂）。 选择用于研究作为HIV RT抑制的前药的化合物是 立体化学定义的新型脱氧核苷，其携带 在碳水化合物部分和那些设计为达特 抑制剂是手性杂环系统，属于 氨基苯并二氮杂卓家族 有证据表明， 对两个抑制剂家族都有活性。 此外， 选择这些化合物进行研究，在相关的情况下， 磷酸化、细胞稳定性、生物利用度 和宿主细胞毒性。 合成工作将涉及开发 这两种化合物家族的方法， 以立体化学定义的光学纯形式产生。 表征，包括最终靶分子的立体化学 将通过多核核磁共振光谱学、高分辨率FAB 质谱、紫外和光学活性数据、元素分析和 单晶X射线数据。 稳定性研究，包括行为 对选定的核苷和核苷酸代谢酶将是 研究了 高度纯化形式的协同抗病毒研究 的目标化合物，其衍生物和前药形式将是 对HIV-1、HIV-2和耐药HIV分离株进行了研究。 一 将在毒性试验中使用一些细胞系，对HIV-1 p24进行抑制 Gag蛋白，抑制HIV RT，抑制前病毒DNA 合成，抑制达特，和治疗指数将是 确定和分析。 细胞联合药物治疗研究 特别是涉及协同抑制HIV的那些， 抗病毒活性的手性氨基苯并二氮杂（达特抑制剂）和新的 或已知的活性核苷和核苷酸（HIV RT抑制剂）， 计划好了 所提出的化合物具有很高的可能性， 抗病毒有用，调查将有助于填补一些 这方面的知识差距。

The long term goals of this research program are to contribute tot he discovery of new generation nucleosides and heterocyclic systems with useful therapeutic potential against the infectivity of HIV-1, HIV-2 and drug-resistant HIV variants. The specific aims of this proposal are the synthesis and anti-HIV studies of novel compounds that are designed to be inhibitors of two phases of the life cycle of HIV, an early phase involving reverse transcription (HIV RT inhibitors) and a later phase involving transcriptional HIV gene expression (Tat inhibitors). Compounds chosen for investigation as pro-drugs for HIV RT inhibition are stereochemically defined, novel deoxygenated nucleosides that carry hypermodification in the carbohydrate moiety and those designed as Tat inhibitors are chiral heterocyclic systems belonging to the aminobenzodiazepine family. There is documentation for potent anti-HIV activity for both families of inhibitors. In addition, the rationale for the selection of these compounds for study includes, where relevant, considerations of phosphorylation, cellular stability, bioavailability and host cell toxicity. The synthetic work will involved the development of approaches to both families of compounds so that they could be produced in stereochemically defined, optically pure forms. Characterization including stereochemistry of the final target molecules will be performed by multinuclear NMR spectroscopy, high resolution FAB mass spectrometry, UV and optical activity data, elemental analysis and single crystal X-ray data. Stability studies including the behavior toward selected nucleoside and nucleotide metabolizing enzymes will be investigated. Collaborative antiviral studies of highly purified forms of the target compounds, their derivatives and pro-drug forms will be carried out against HIV-1, HIV-2 and drug-resistant HIV isolates. A number of cell lines will be used in toxicity, on inhibition of HIV-1 p24 Gag protein, on inhibition of HIV RT, on inhibition of proviral DNA synthesis, on inhibition of Tat, and on therapeutic indexes will be determined and analyzed. Cellular combination drug therapeutic studies particularly those involving synergistic inhibition of HIV with antivirally active chiral aminobenzodiazepines (Tat inhibitors) and new or known active nucleosides and nucleotides (HIV RT inhibitors) ar planned. The proposed compounds have a high probability of being antivirally useful and the investigation will contribute to filling some of the gaps in knowledge in this area.