(-)-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 alpha(2B) adrenoceptor, with an EC50 of 4.2 mu M. 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. (C) 2009 Elsevier Ltd. All rights reserved.