SYNTHESIS OF PRADIMICIN A AND RELATED ANTI-HIV AGENTS.

制定有效的方法预防和治疗 艾滋病是目前医学面临的最紧迫的挑战之一。 的 天然产物普拉米星/苯那霉素家族的最新发现 提供了一个重要的制药线索 对于普拉米星A及其 同源物表现出抑制感染的能力， 人类免疫缺陷病毒（HIV）的扩散。 而且这 化合物家族在治疗 全身性真菌感染-第二个经常致命的疾病， 临床上有效的药物很少。 这项建议有两个目标。 第一是阐述 普拉米星A及其同系物的有效全合成， 合成类似物的方法。 第二个同样重要的目标 是开发一种人造“酶”，通过一次操作， 从相对丰富的天然产物中获得关键前体 用于制备其他方法难以获得的类似物。 的 人工酶被设计成水解酰胺键， 目前被常规方法或天然酶切割 而不会在基底的其他地方造成严重破坏。 人工酶 也应该直接应用于肽测序。 将对本项目过程中产生的化合物进行评价， 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.