PHOSPHORYLATED ISONUCLEOSIDES--NEW ANTIHIV AGENTS

这项研究计划的长期目标是促进 新核苷、核苷酸及相关化学和生物化学 具有针对感染性的有用治疗潜力的分子， 艾滋病病毒，包括抗药性艾滋病毒变种。 的具体目标 该提案是设计，合成，酶学和抗艾滋病毒的研究 结构和功能相关家族的磷酸化类似物， 立体化学定义的化合物称为异二脱氧核苷， 有一些文献证明它具有很强的抗艾滋病毒活性。 选择这些化合物进行研究的依据包括， 此外，考虑磷酸化，包括在体内， 磷酸化，细胞稳定性，生物利用度， 掺入病毒DNA和抑制HIV逆转录酶， 和宿主细胞毒性。 合成工作将涉及开发 光学纯、新型异二酰核苷及其合成方法 转化成磷酸盐、亚甲基膦酸盐、H-膦酸盐， 包括各种掩蔽的前药的氨基磷酸酯和三磷酸酯 forms. 完整的表征，包括最终产物的立体化学 产物将通过（31）P、（13）C、（1）H和（15）N NMR进行 光谱、高分辨率FAB质谱、UV和光学 活性数据、元素分析和单晶X射线数据。 所有目标化合物的稳定性，包括对 选择核苷代谢酶，将进行研究。 高度纯化形式的抗病毒合作研究 磷酸化的目标化合物，它们的前药形式，母体 异二脱氧核苷和它们的酰化亲脂性衍生物， 针对HIV-1、HIV-2和AZT耐药HIV毒株进行。 一些 的细胞系将用于这些研究，包括MT 2、MT4、ATH 8和 H9。 在MT 2、MT4和MT5中抑制HIV细胞病变效应的数据 ATH 8细胞系，对宿主细胞的细胞毒性，对 H9细胞中HIV-1 p24 Gag蛋白对前病毒DNA合成的抑制作用 在外周血单核细胞，并对治疗指数将 确定和分析。 所提出的化合物具有很高的概率， 具有有用的抗HIV活性，研究将有助于 填补了这一领域的一些知识空白。

The long term goals of this research program are to contribute to the chemistry and biochemistry of novel nucleosides, nucleotides and related molecules with useful therapeutic potential against the infectivity of the AIDS viruses, including drug-resistant HIV variants. The specific aims of this proposal are the design, synthesis, enzymology and anti-HIV studies of the phosphorylated analogs of related families of structurally and stereochemically defined compounds referred to as isodideoxynucleosides, for which there is some documentation for strong anti-HIV activity. Rationale for the selection of these compounds for investigation includes, in addition, considerations of phosphorylation including in vivo phosphorylation, cellular stability, bioavailability, selectivity of incorporation into viral DNA and inhibition of HIV reverse transcriptase, and host cell toxicity. The synthetic work will involve development of approaches to optically pure, novel isodideoynucleosides and their conversion to phosphates, methylenephosphonates, H-phosphonates, phosphoramidates and triphosphates including various masked pro-drugs forms. Complete characterization including stereochemistry of the final products will be performed by (31)P, (13)C, (1)H and (15)N NMR spectroscopy, high-resolution FAB mass spectrometry, UV and optical activity data, elemental analysis, and single crystal X-ray data. Stabilities of all target compounds, including the behavior towards selected nucleoside metabolizing enzymes, will be investigated. Collaborative antiviral studies of highly purified forms of the phosphorylated target compounds, their pro-drugs forms, the parent isodideoxynucleosides and their acylated lipophilic derivatives, will be carried out against HIV-1, HIV-2, and AZT-resistant HIV strains. A number of cell lines will be used in these studies including MT2, MT4, ATH8 and H9. Data on inhibition of the cytopathic effect of HIV in MT2, MT4 and ATH8 cell lines, on host cell cytotoxicity, on inhibition of expression of HIV-1 p24 Gag protein in H9 cells, on inhibition of proviral DNA synthesis in peripheral blood mononuclear cells, and on therapeutic indexes will be determined and analyzed. The proposed compounds have a high probability of having useful anti-HIV activity and the investigation will contribute to filling some of the gaps in knowledge in this area.