SYNTHESIS OF NEW ANTIHIV AGENTS RELATED TO COSALANE

描述(改编自摘要)：尽管取得了重大进展 最近在艾滋病的化疗中做出了，目前可用的， 临床上有用的抗艾滋病药物只针对两种生物 大分子、逆转录酶和蛋白酶。因此，新的 需要抗艾滋病药物，这些药物将与其他病毒相互作用 目标是病毒复制周期中重要的目标。这些新特工 有了新的行动机制，可以预期增强 通过联合化疗成功治疗艾滋病。 这位首席调查员和他的同事最近的工作涉及 一种新型抗HIV药物Coralane的设计与合成 CD4与gp120的结合并抑制HIV-1的细胞病变效应 细胞培养中的HIV-2。尽管围绕抗病毒药物的热情 柯萨林活性高，其潜在的治疗用途是 受制于口服生物利用度低和效力未优化。现在 应用程序用于支持设计和合成某些Cosalane类似物 这将带来这些遗留的问题。 为了解决口服生物利用度低的问题，一系列 提出了Cosalane类似物和前药，其中化合物是 旨在增强口服吸收和提高代谢稳定性。 这些化合物的代谢将在大鼠的肠道和 肝微体系统以及肠系膜和全身血液 对整只动物进行采样。药代动力学将被定义， 代谢物的结构将被确定，代谢物将 是人工合成的。 设计和合成更有效的Cosalane类似物也在进行中 被执行。这些努力得到了计算机图形学的帮助 假想的配体-蛋白质复合体的分子模拟，以及通过 关于结构参数的现有信息的分析 与宇宙丙烷类似物的生物活性有关 到目前为止合成的。科萨拉烷的同系物将被检测出一定数量 生物活动，包括：(1)预防艾滋病毒-1细胞病变 在细胞培养中；(2)细胞毒性；(3)抑制合体形成； (4)抑制病毒粒子与细胞的结合；(5)CD4结合；(6)gp120 结合；(7)抑制gp120-CD4结合；(8)抑制HIV-1RT；(9) 抑制整合酶；(10)抑制蛋白酶；(11)时间的影响 附加、有限处理和预孵化对活性的影响；(12)对 病毒产生；(13)血清和血清蛋白结合的稳定性；以及 (14)体内中空纤维动物模型的活性。

DESCRIPTION (adapted from the Abstract): Although significant advances have been made recently in the chemotherapy of AIDS, the presently available, clinically useful anti-AIDS agents target only two biological macromolecules, reverse transcriptase and protease. Therefore, new anti-AIDS agents are needed which will interact with additional viral targets important in the replication cycle of the virus. These new agents with novel mechanisms of action can be expected to enhance the prospects for successful treatment of AIDS by combination chemotherapy. Recent work by this Principal Investigator and his associates has involved the design and synthesis of cosalane, a novel anti-HIV agent which inhibits the binding of CD4 to gp120 and inhibits the cytopathic effects of HIV-1 and HIV-2 in cell cultures. Although enthusiasm surrounding the antiviral activity of cosalane is high, the potential therapeutic use of cosalane is restricted by low oral bioavailability and unoptimized potency. The present application is for support to design and synthesize certain cosalane analogs which will broach these remaining problems. In order to address the problem of low oral bioavailability, a series of cosalane analogs and prodrugs is proposed in which the compounds are designed to have enhanced oral absorption and increased metabolic stability. The metabolism of these compounds will be studied in rat intestinal and hepatic microsomal systems as well as by mesenteric and systemic blood sampling in whole animals. The pharmacokinetics will be defined, the structures of the metabolites will be determined, and the metabolites will be synthesized. The design and synthesis of more potent cosalane analogs is also being carried out. These efforts are being assisted by computer graphics molecular modeling of hypothetical ligand-protein complexes, as well as by analysis of the available information concerning the structural parameters associated with the biological activities of the cosalane analogs synthesized to date. The cosalane congeners will be examined for a number of biological activities, including: (1) prevention of HIV-1 cytopathicity in cell culture; (2) cytotoxicity; (3) inhibition of syncytium formation; (4) inhibition of virion binding to cells; (5) CD4 binding; (6) gp120 binding; (7) inhibition of gp120-CD4 binding; (8) HIV-1 RT inhibition; (9) inhibition of integrase; (10) inhibition of protease; (11) effect of time of addition, limited treatment, and preincubation on activity; (12) effects on virus production; (13) stability in serum and serum protein binding; and (14) activity in an in vivo hollow fiber animal model.