Acroamine A, a 2-Amino Adenine Alkaloid from the Marine Soft Coral Acrozoanthus australiae and Its Semisynthetic Derivatives That Inhibit cAMP-Dependent Protein Kinase A Catalytic Subunit Alpha.

A high throughput screen performed to identify catalytic inhibitors of the oncogenic fusion form of cAMP-dependent protein kinase A catalytic subunit alpha (J-PKAcα) found an individual fraction from an organic extract of the marine soft coral Acrozoanthus australiae as active. Bioassay-guided isolation led to the identification of a 2-amino adenine alkaloid acroamine A ( 1 ), the first secondary metabolite discovered from this genus and previously reported as a synthetic product. As a naturally occurring protein kinase inhibitor, to unambiguously assign its chemical structure using modern spectroscopic and spectrometric techniques, five N -methylated derivatives acroamines A 1 -A 5 ( 2 - 6 ) were semisynthesized. Three additional brominated congeners A 6 -A 8 ( 7 - 9 ) were also semisynthesized to investigate the structure-activity relationship of the nine compounds as J-PKAcα inhibitors. Compounds 1 - 9 were tested for J-PKAcα and wild-type PKA inhibitory activities, which were observed exclusively in acroamine A ( 1 ) and its brominated analogs ( 7 - 9 ) achieving moderate potency (IC 50 2-50 μM) while none of the N -methylated analogs exhibited kinase inhibition.