SYNTHESIS OF PRADIMICIN A AND RELATED ANTI-HIV AGENTS.

开发有效的预防和治疗方法 艾滋病是目前医学面临的最紧迫的挑战之一。这个 新近发现的天然产物普拉米星/苯诺米星家族 已经提供了一个重要的药物先导。用于帕拉米星A及其 同系物表现出抑制感染的能力-以及随后的 --人类免疫缺陷病毒(HIV)的扩散。此外，这一点 一系列化合物也显示出令人印象深刻的疗效 系统性真菌感染--第二种通常致命的疾病，有 很少有临床有效的药物。 这项提议有两个目标。第一个是对 帕拉米星A及其同系物的高效全合成 类似物的合成方法。第二个，但同样重要的目标 就是开发一种人造“酶”，它应该--通过一个简单的操作-- 从相对丰富的天然产品中获得关键前体 用于制备以其他方式仅难以获得的类似物。这个 人工酶被设计用来水解酰胺键，而这种键不能 目前可用常规方法或天然酶进行切割 而不会在衬底的其他地方造成严重破坏。人造酶 还应直接应用于多肽测序。 在这个项目的过程中产生的化合物将被评估 抗HIV和抗真菌活性。

The development of effective methods for the prevention and treatment of AIDs is one of the most pressing challenges presently facing medicine. The recent discovery of the pradimicin/benanomicin family of natural products has provided an important pharmaceutical lead. For pradimicin A and its congeners exhibit the ability to inhibit infection by - and subsequent proliferation of - human immunodeficiency virus (HIV). Moreover, this family of compounds also display impressive efficacy in the treatment of systemic fungal infections - second often-fatal disease for which there are few clinically effective drugs. This proposal has two objectives. The first is the elaboration of efficient total syntheses of pradimicin A and its congeners that pave the way for the synthesis of analogs. The second, but equally important goal is to develop an artificial "enzyme" that should - by a single operation - make available from the relatively abundant natural products key precursors for the preparation of otherwise only difficultly accessible analogs. The artificial enzyme is designed to hydrolyze an amide bond which cannot presently be cleaved be either conventional methods or natural enzymes without wreaking havoc elsewhere in the substrate. The artificial enzyme should also have direct application to peptide sequencing. Compounds generated during the course of this project will be evaluated for anti-HIV and antifungal activity.