Secondary metabolites from marine invertebrates and microbes with activity against HIV.

Mark T. Hamann. The University of Mississippi, School of Pharmacy, University, MS 38677 (USA).

Background: Perhaps, the most significant anti-HIV leads of marine origin reported thus far is the nucleoside ara-A. Ara-A is a semisynthetic compound based on the arabinosyl nucleosides isolated from the sponge Cryptotethia crypta.  Ara-A or Vidarabine was synthesized and later produced by fermentation of Streptomyces griseus. Ara-A has since been isolated from a Mediterranean gorgonian Eunicella cavolini in 1984.  Once it was realized that biological systems would recognize the nucleoside base after modifications of the sugar moiety, chemists began to substitute the typical pentoses with acyclic entities or with substituted sugars leading to the drug azidothymidine (AZT). Ara-A, ara-C, acyclovir and AZT have gone into clinical use and are all examples of products of semisynthetic modifications of the arabinosyl nucleosides. Material and Methods: Marine invertebrates, algae and microorganisms collected globally have been evaluated for secondary metabolites with activity against HIV.  The active metabolites are characterized using NMR spectroscopy and MS.  Those leads with activity against HIV are then subjected to a series of standard and relatively high-throughput semisynthetic modifications. Results: Many of these extraordinarily sophisticated and anti-HIV marine natural products can be isolated in significant quantities without great difficulty.  As a result these readily available HIV active natural products provide valuable starting materials for the rational generation of libraries of compounds prepared through semisynthesis and biocatalysis. A review of our work using marine natural products to generate rationally designed compound libraries and their biological activity against HIV will be presented.  The marine natural products utilized to date as starting materials consist of compounds from a variety of structural classes and include: aureol, puupehenone, sarcophine, palinurin, and the manzamine alkaloids. Conclusion: The possibility to generate diverse bioactive products beginning with a marine natural product scaffold is a direct result of improvements made in the technologies to harvest samples from the ocean, purify, assay and characterize complex natural products quickly and complete chemical reactions and biotransformations in parallel.  As a result the vast resources of the ocean can now be utilized routinely to design and produce countless products to be evaluated as part of drug discovery and development programs for HIV and AIDS OI.