Peloruside A and B are 16-membered macrolactones, isolated in minute quantities as secondary
metabolites from the marine sponge Mycale hentscheli. Both have been shown to be cytotoxic in
the low nanomolar range via a strong microtubule-stabilizing interaction, comparable to that of
paclitaxel. Due to the low natural abundance as well as the long, complex total syntheses;
peloruside is not suited for large-scale pharmaceutical applications. Pelofen B, the phenyl
analogue of peloruside B, was developed and successfully synthesized by our research group. This
simplified analogue was evaluated for its biological activity and was shown to retain its
cytotoxicity. As this analogue can be more easily synthesized, it has been chosen as the lead
compound for the discovery of the structure-activity relationship of peloruside / Pelofen as well as
the development of stronger analogues. Recently, a new and improved synthetic route, based on a
late-stage ring-closing metathesis, towards Pelofen B was successfully developed.
This research application proposes the synthesis of a variated series of analogues based upon the
aforementioned synthetic route, via late-stage diversification and/or using differentiated building
blocks, which will be evaluated for their biological activity. The synthesized analogues will serve to
make significant contributions to the pharmacophores and SAR of peloruside and Pelofen B, as
well as possibly becoming new, improved chemotherapeutic agents.