SYNTHESIS OF NEW ANTIHIV AGENTS RELATED TO COSALANE

描述（改编自摘要）：设计，合成， 评价治疗获得性肺炎的新治疗剂 免疫缺陷综合症（艾滋病）是目前面临的一个重大挑战， 科学界。 该研究小组最近的工作导致了 合成一种新的抗人类免疫缺陷病毒的药物， 1型（HIV）的代理商称为Cosalane。 对抗艾滋病病毒的热情 科沙拉恩的活性一直很高，这一事实证明， 达到决策网络（DN）第二阶段的发展阶段， 国家癌症研究所，相当多的资源已经 已投资于其规模扩大的合成，以获得足够的 用于临床研究的材料。 可沙拉宁对所有菌株都有活性， 艾滋病毒检测，包括对齐多夫定（AZT）耐药的人， 非核苷逆转录酶（RT）抑制剂。 初步研究 已经表明，柯沙拉烷抑制病毒与 细胞膜以及结合后融合事件。 研究提出， 在本申请中用于合成柯柳烷衍生物， 类似物，旨在解决一些重要问题， 与柯柳烷的临床前开发有关。 特别是具有一种 本研究的主要目的是提高 通过利用前药方法制备可沙拉烷。 此外，本发明还提供了一种方法， 将尝试合成更亲脂的柯柳烷类似物 它保留了柯沙拉烷的抗病毒活性， 口服后更容易吸收。 先导药物优化 通过对柯沙拉烷类似物的研究，也将得到高度重视。 一个 将合成并评价一系列柯柳烷类似物， 探索与抗HIV活性相关的结构参数 还可获得具有增加的可药用活性的其它化合物， 效力和毒性降低。 结构参数为 所检查的包括连接体链从连接体链的连接点。 将二辛基甲烷部分连接到类固醇核，连接体的长度 链，用二氯二辛基甲烷部分取代二氯二辛基甲烷部分， 三水杨基甲烷单位，并与其他类固醇的替代 膜靶向结构片段，包括简单的磷脂， 醚脂质和两性离子烷基甘油衍生物。 在这项工作中， 目前的合作，以评估柯沙拉烷类似物作为抗艾滋病毒 特工将继续。 目前正在进行的试验， 合作的基础包括预防艾滋病毒细胞病变， 未感染细胞的细胞毒性，合胞体形成的抑制， 抑制病毒粒子与细胞结合、CD 4结合、gp 120结合、 gp 120-CD 4结合的抑制，RT的抑制， 整合酶和蛋白酶的抑制。 此外，实验将 在添加、有限处理、预孵育、 抑制病毒产生、血浆蛋白结合和稳定性 血清的存在和酸性条件下，口服生物利用度， 药代动力学和前药代谢。 的有效性 还将评价所提出的前药策略。

DESCRIPTION (adapted from the Abstract): The design, synthesis, and evaluation of new therapeutic agents for the treatment of the acquired immunodeficiency syndrome (AIDS) is a significant challenge now facing the scientific community. Recent work by this research group has resulted in the synthesis of a novel agent against the human immunodeficiency virus, Type 1 (HIV) agent called cosalane. Enthusiasm about the anti-HIV activity of cosalane has been high, as evidenced by the fact that it has reached the Decision Network (DN) Stage II developmental stage at the National Cancer Institute, and that considerable resources have already been invested in its scaled-up synthesis in order to obtain sufficient material for clinical studies. Cosalane is active against all strains of HIV tested, including those resistant to zidovudine (AZT) and non-nucleoside reverse transcriptase (RT) inhibitors. Initial studies have indicated that cosalane inhibits both the binding of the virus to the cell membrane as well as postbindlng fusion events. The research proposed in this application is for the synthesis of cosalane derivatives and analogues that have been designed to address a number of important issues related to the preclinical development of cosalane. In particular, one of the main goals of this research is to improve the oral bioavailability of cosalane through the utilization of a prodrug approach. In addition, attempts will be made to synthesize more lipophilic cosalane analogues which retain the antiviral activity of cosalane and would presumably be more readily absorbed after oral administration. Lead optimization through the study of cosalane analogs will also receive high priority. An array of cosalane analogs will be synthesized and evaluated in order to probe the structural parameters associated with the anti-HIV activity of cosalane and also to obtain additional compounds having increased potencies and decreased toxicities. The structural parameters to be examined include the point of attachment of the linker chain from the disalicylmethane moiety to the steroid nucleus, the length of the linker chain, the replacement of the dichlorodisalicylmethane moiety with a trisalicylmethane unit, and the replacement of the steroid with other membrane-targeting structural fragments, including simple phospholipids, ether lipids, and zwitterionic alkylglycerol derivatives. In this work, present collaborations for evaluation of cosalane analogs as anti-HIV agents will continue. The assays presently being performed on a collaborative basis include the prevention of HIV cytopathicity, the cytotoxicity in uninfected cells, the inhibition of syncytium formation, the inhibition of virion binding to cells, CD4 binding, gp120 binding, the inhibition of gp120- CD4 binding, the inhibition of RT, the inhibition of integrase, and the inhibition of protease. In addition, experiments will be done on time of addition, limited treatment, preincubation, the inhibition of virus production, plasma protein binding, and stability in the presence of serum and under acidic conditions, oral bioavailability, pharmacokinetics, and prodrug metabolism. The effectiveness of the proposed prodrug strategies will also be evaluated.