(−)-Dibromophakellin: An α2B adrenoceptor agonist isolated from the Australian marine sponge, Acanthella costata

Bioassay-guided fractionation of the organic extract from the marine sponge Acanthella costata resulted in the isolation of the known natural product, (−)-dibromophakellin (1). Using a fluorescence imaging plate reader (FLIPR) based assay, compound 1 was identified as displaying agonist activity against the α2B adrenoceptor, with an EC50 of 4.2 μM. Debromination and Suzuki–Miyaura coupling reactions were undertaken in order to provide structure activity data about the pyrrole ring of this marine metabolite. These synthetic studies generated the known natural product analogues, (−)-phakellin (2), and (−)-monobromophakellin (3), along with the new synthetic derivatives (−)-4-bromo-5-phenylphakellin (5) and (−)-4,5-diphenylphakellin (6). Substitution of the C-5 Br of 1 with H (2 and 3) or phenyl (5 and 6) resulted in loss of activity indicating that Br at C-5 is required for agonist activity.

Bioassay-guided fractionation of the organic extract from the marine sponge Acanthella costata identified (−)-dibromophakellin (1) as an α2B adrenoceptor agonist, with an EC50 of 4.2 μM. A series of small-scale synthetic reactions were performed on this marine natural product in order to provide SAR data about the pyrrole ring.Figure optionsDownload as PowerPoint slide