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， 临床上有用的抗艾滋病剂仅靶向两种生物活性物质， 大分子、逆转录酶和蛋白酶。 因此，新 需要抗艾滋病药物， 病毒复制周期中的重要目标。 这些新探员 与新的作用机制，可以预期将提高前景， 联合化疗成功治疗艾滋病。 该首席研究员及其同事最近的工作涉及 新型抗HIV药物可莎烷的设计与合成 CD 4与gp 120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 由于柯沙拉烷的活性高，因此其潜在的治疗用途是 受口服生物利用度低和效力未优化的限制。 本 应用是为了支持设计和合成某些柯柳烷类似物 这将解决这些遗留问题。 为了解决口服生物利用度低的问题， 提出了柯柳烷类似物和前药，其中所述化合物 设计成具有增强的口服吸收和增加的代谢稳定性。 这些化合物的代谢将在大鼠肠道和 肝微粒体系统以及肠系膜和全身血液 在整个动物中取样。 将定义药代动力学， 将确定代谢物的结构，并且代谢物将 合成。 更有效的柯柳烷类似物的设计和合成也在进行中。 贯彻 这些努力得到了计算机图形学的帮助 假设配体-蛋白质复合物的分子建模，以及 分析有关结构参数的可用信息 与柯柳烷类似物的生物活性相关 合成至今。 将对柯沙拉烷同系物进行检查， 生物活性，包括：（1）预防HIV-1细胞病变 在细胞培养中;（2）细胞毒性;（3）抑制合胞体形成; (4)抑制病毒粒子与细胞的结合;（5）CD 4结合;（6）gp 120 结合;（7）抑制gp 120-CD 4结合;（8）抑制HIV-1 RT;（9） 整合酶的抑制;（10）蛋白酶的抑制;（11） 添加、有限处理和预孵育对活性的影响;（12）对 （13）在血清中的稳定性和血清蛋白结合;和 (14)在体内中空纤维动物模型中的活性。

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.