Total synthesis and biological evaluation of the marine bromopyrrole alkaloid dispyrin: elucidation of discrete molecular targets with therapeutic potential.
The first total synthesis of dispyrin, a recently reported bromopyrrole alkaloid from Agelas dispar with an unprecedented bromopyrrole tyramine motif, was achieved in three steps on a gram scale (68.4% overall). No biological activity was reported for dispyrin, so we evaluated synthetic dispyrin against>200 discrete molecular targets in radioligand binding and functional assays. Unlike most marine natural products, dispyrin (1) possesses no antibacterial or anticancer activity, but was found to be a potent ligand and antagonist of several therapeutically relevant GPCRs, the alpha1D and alpha2A adrenergic receptors and the H2 and H3 histamine receptors.
Kennedy
J Phillip
JP
Department of Chemistry, Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Vanderbilt Medical Center, Nashville, TN 37232-6600, USA.
Brogan
John T
JT
Lindsley
Craig W
CW
D000322:Adrenergic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047230:Agelas / Q000737:chemistry*; D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D004354:Drug Screening Assays, Antitumor; D018494:Histamine Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006842:Hydrocarbons, Brominated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008386:Marine Biology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists
D000322:Adrenergic Agonists; D000470:Alkaloids; D018494:Histamine Agents; D006842:Hydrocarbons, Brominated; D008024:Ligands; D011758:Pyrroles; D043562:Receptors, G-Protein-Coupled; C519748:dispyrin