Synthesis of the Palmerolides

The vast marine ecosystem has become a prolific source of structurally diverse and bioactive secondary metabolites over the last three decades. The biological activities displayed by many of these secondary metabolites is often startling, demonstrating, for example, potent cytotoxic, antibiotic, pesticidal and antifungal properties. Today, there remains a pressing demand for the continual development of new drugs with the onset of antibiotic resistance in bacterial diseases and the problem of multi-drug resistance in cancer treatment. As a result, bioactive marine natural products, with their unique modes of action and potent activities, continue to have great potential as lead compounds for the development of new generation pharmaceuticals. The low natural abundance, however, of many of these compounds isolated from rare marine species requires that alternative means of supply are required to enable further biological evaluation, in which total synthesis continues to provide a powerful solution, while inspiring the development of new synthetic methodology. In conjunction, total synthesis can unambiguously confirm the initial structural assignment of a new natural product, while providing an opportunity to introduce molecular diversity through the design of simplified analogues, which may have more desirable pharmacological properties in terms of efficacy and safety.The Antarctic seas have remained largely unexplored until very recently, due primarily to their extreme isolation and climate. However, they have evolved a largely indigenous population of invertebrate fauna and algae with rich biodiversity which have adapted to the cold and developed unusual chemical defence mechanisms to combat predators. This research programme targets the synthesis of the palmerolides- a family of cytotoxic marine macrolides isolated from the rare Antarctic tunicate Synoicum adareanum collected in the shallow waters surrounding Anvers Island on the Antarctic Peninsula. The parent member of this family, palmerolide A displays significantly increased selectivity for melanoma cancer cell lines. Further biological screening revealed palmerolide A to inhibit vacuolar-ATPase, although the precise mechanism of action remains unknown at present, and demonstrated in vivo activity in the NCI's hollow-fibre assay. As such, palmerolide A has great potential for development as a new cancer therapeutic and a programme of research towards its synthesis and analogues, will alleviate the supply issue providing material for further biological studies, unambiguosly define the absolute structure and serve as a scaffold for the design of analogues for structure activity relationship studies, in order to elucidate the key structural features required for biological activity.