TRICIRIBINE AND NOVEL ANALOGS AS INHIBITORS OF HIV

三氯硝胺(TCN)及其水溶性前药(TCN-5‘-单磷酸， TCN-P)已作为抗癌药物进行研究；II期临床试验 正在与TCN-P合作。这两种化合物都不会被代谢成双- 或三磷酸，不结合到核酸中。最近我们 发现TCN和TCN-P具有抗人类免疫缺陷的活性 病毒(HIV)在急性感染和慢性感染的T细胞中和 纳摩尔浓度的单核/巨噬细胞。这些浓度 至少比那些对细胞有毒性的要低一千倍 未受感染的人类细胞。活动还针对一个小组进行了演示 HIV-1和HIV-2临床分离株。HIV对齐多夫定(AZT)的耐药性 对TCN或TCN-P不交叉抗性，分离反向 转录酶(RT)不受TCN及其核苷酸的抑制 表明该化合物不是通过这种机制起作用的。 基于这些新发现，这项提议的广泛目标是 以TCN为先导化合物，发明具有更大容量的新试剂 艾滋病毒的活性和选择性。一种系统的化学程序 合成新的TCN类似物旨在开发新的化合物 将对其进行抗艾滋病毒活性和细胞毒性评估 人类细胞。再加上对TCN行动模式的审查 针对艾滋病毒，这些研究应该允许设计和合成 比母体更活跃和/或毒性更小的化合物 化合物。 具体目标包括合成TCN的新的同系物，包括 但不限于：(I)杂环取代类似物， (Ii)糖类似物；(Iii)环状修饰化合物；及(Iv)C- 核苷。化学合成的指导将由以下人员提供 新化合物的抗病毒和细胞毒性评价。评估 将包括在急性感染细胞中的合胞体空斑分析和一项 或使用急性和慢性感染的下列方法中的一种以上 T细胞、单核/巨噬细胞或外周血白细胞(PBL)： 感染性病毒产量减少、p24核心抗原或RT检测。 将结合现有的TCN和活性类似物进行研究 抗病毒药物用于确定是否增强了抗HIV-1的活性 在没有伴随细胞毒性增强的情况下发生。数据将是 使用由开发的三维剂量-反应方法进行分析 美国和统计上有显著协同(或对立)的地区将是 进行鉴定和量化。

Triciribine (TCN) and its water soluble prodrug (TCN-5'-monophosphate, TCN-P) have been studied as anticancer drugs; phase II clinical trials are in progress with TCN-P. Neither compound is metabolized to the di- or triphosphate and is not incorporated into nucleic acids. Recently we discovered that TCN and TCN-P are active against human immunodeficiency virus (HIV) in acutely infected and chronically infected T-cells and monocyte/macrophages at nanomolar concentrations. These concentrations are at least a thousand-fold lower than those which are cytotoxic in uninfected human cells. Activity also was demonstrated against a panel of HIV-1 and HIV-2 clinical isolates. HIV resistant to zidovudine (AZT) was not cross-resistant to TCN or TCN-P and isolated reverse transcriptase (RT) was not inhibited by TCN nor its nucleotides demonstrating that the compound does not act via this mechanism. Based upon these new discoveries, the broad objective of this proposal is to use TCN as a lead compound and invent new agents having greater activity and selectivity for HIV. A systematic program of chemical synthesis of new TCN analogs has been designed to develop novel compounds which will be evaluated for activity against HIV and for cytotoxicity in human cells. Coupled with an examination of the mode of action of TCN against HIV, these studies should permit the design and synthesis of compounds which are more active and/or less toxic than the parent compounds. The specific aims involve the synthesis of new congeners of TCN including but not limited to the following: (i) heterocycle-substituted analogs, (ii) sugar analogs, (iii) ring-modified compounds, and (iv) C-- nucleosides. Direction for the chemical synthesis will be provided by antiviral and cytotoxicity evaluation of the new compounds. Evaluations will include a syncytial plaque assay in acutely infected cells and one or more of the following methods using acutely and chronically infected T-cells, monocyte/macrophages, or peripheral blood leukocytes (PBL): infectious virus yield reduction, p24 core antigen, or RT assays. TCN and active analogs will be studied in combination with existing antiviral drugs to determine if potentiation of activity against HIV- 1 occurs without a concomitant potentiation of cytotoxicity. Data will be analyzed using three-dimensional dose-response methodology developed by us and areas of statistically significant synergy (or antagonism) will be identified and quantitated.