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.
