Acroamine A,\na 2‑Amino Adenine Alkaloid from\nthe Marine Soft Coral <i>Acrozoanthus australiae</i> and\nIts Semisynthetic Derivatives That Inhibit cAMP-Dependent Protein\nKinase A Catalytic Subunit Alpha

A high throughput screen performed to identify catalytic\ninhibitors\nof the oncogenic fusion form of cAMP-dependent protein kinase A catalytic\nsubunit alpha (J-PKAcα) found an individual fraction from an\norganic extract of the marine soft coral <i>Acrozoanthus australiae</i> as active. Bioassay-guided isolation led to the identification of\na 2-amino adenine alkaloid acroamine A (<b>1</b>), the first\nsecondary metabolite discovered from this genus and previously reported\nas a synthetic product. As a naturally occurring protein kinase inhibitor,\nto unambiguously assign its chemical structure using modern spectroscopic\nand spectrometric techniques, five <i>N</i>-methylated derivatives\nacroamines A<sub>1</sub>–A<sub>5</sub> (<b>2</b>–<b>6</b>) were semisynthesized. Three additional brominated congeners\nA<sub>6</sub>-A<sub>8</sub> (<b>7</b>–<b>9</b>)\nwere also semisynthesized to investigate the structure–activity\nrelationship of the nine compounds as J-PKAcα inhibitors. Compounds <b>1</b>–<b>9</b> were tested for J-PKAcα and\nwild-type PKA inhibitory activities, which were observed exclusively\nin acroamine A (<b>1</b>) and its brominated analogs (<b>7</b>–<b>9</b>) achieving moderate potency (IC<sub>50</sub> 2–50 μM) while none of the <i>N</i>-methylated analogs exhibited kinase inhibition.