(-)-Dibromophakellin: an alpha2B adrenoceptor agonist isolated from the Australian marine sponge, Acanthella costata

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 6; pp. 2497 - 2500
• Main Authors: Davis, Rohan A, Fechner, Gregory A, Sykes, Melissa, Garavelas, Agatha, Pass, David M, Carroll, Anthony R, Addepalli, Rama, Avery, Vicky M, Hooper, John N A, Quinn, Ronald J
• Format: Journal Article
• Language: English
• Published: England 15.03.2009
• Subjects: Adrenergic alpha-Agonists - isolation & purification; Adrenergic alpha-Agonists - pharmacology; Animals; Australia; Cell Line; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Porifera - chemistry; Spectrophotometry, Ultraviolet; Structure-Activity Relationship
• ISSN: 1464-3391
• DOI: 10.1016/j.bmc.2009.01.065

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 EC(50) of 4.2muM. 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.