PHOSPHORYLATED ISONUCLEOSIDES--NEW ANTI-HIV AGENTS

这项研究计划的长期目标是为 新型核苷、核苷酸及其相关化合物的化学和生物化学 具有有效治疗潜力的分子，以对抗病毒的传染性 艾滋病病毒，包括具有抗药性的艾滋病毒变种。的具体目标 这项建议是设计，合成，酶学和抗艾滋病毒的研究 结构和结构上相关家族的磷酸化类似物 立体化学定义的化合物称为异双脱氧核苷， 对于它，有一些文件表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理由包括， 此外，对包括体内的磷酸化的考虑 磷酸化，细胞稳定性，生物利用度，选择性 病毒DNA的整合和HIV逆转录酶的抑制， 和宿主细胞毒性。综合工作将涉及开发 光学纯的新型异双核苷及其合成方法 转化为磷酸盐、亚甲基磷酸盐、H-磷酸盐， 磷酰胺酸盐和三磷酸盐，包括各种掩蔽前药 表格。完整的表征，包括最终的立体化学 产物将通过(31)P、(13)C、(1)H和(15)N核磁共振进行 光谱学、高分辨率FAB质谱学、紫外线和光学 活度数据、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 选定的核苷代谢酶，将进行研究。 高度纯化形式的联合抗病毒研究 磷酸化的目标化合物，它们的前药物形式，母体 异二脱氧核苷及其酰化亲脂衍生物将是 针对HIV-1、HIV-2和耐AZT的HIV毒株进行了研究。一个数字 将在这些研究中使用的细胞系包括MT2、MT4、ATH8和 H9.HIV抑制MT2、MT4和MT4细胞病变作用的数据 ATH8细胞株对宿主细胞的细胞毒作用，对其表达的抑制作用 H9细胞中HIV-1 p24 Gag蛋白对前病毒DNA合成的抑制作用 在外周血单核细胞中，对治疗指标的影响 进行了测定和分析。建议的化合物很有可能是 具有有用的抗艾滋病毒活动和调查将有助于 填补了这一领域知识的一些空白。

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.