Synthesis and Cytotoxicity of Ring C-Functionalized Derivatives of the Marine Natural Product (-)-Dibromophakellstatin

A structureactivity relationship study of ring C-functionalized derivatives of the cytotoxic marine natural product()-dibromophakellstatin from the sponge Phakellia mauritiana is reported. Functionalization of the pyrrolidine ring was achieved starting from the hydroxy derivative by conversion to the triflate followed by etherification by epimerizing nucleophilic substitution. We identified (12R)-dibromo-12-hydroxyphakellstatin as the most cytotoxic derivative, which exhibited an average IC50 value of 1.4 mu M against a panel of twelve human cancer cell lines. However, the 12S diastereomer was inactive. Dehydrophakellstatin was synthesized as the first example of a phakellin skeleton with an unsaturated ring C.