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Chloromethylhalicyclamine B, a Marine-Derived Protein Kinase CK1δ/ε Inhibitor

Esposito, Germana, Bourguet-Kondracki, Marie-Lise, Mai, Linh H., Longeon, Arlette, Teta, Roberta, Meijer, Laurent, Van Soest, Rob, Mangoni, Alfonso, Costantino, Valeria
Journal of natural products 2016 v.79 no.11 pp. 2953-2960
alkaloids, inhibitory concentration 50, methylene chloride, protein kinases, spectral analysis
The halogenated alkaloid chloromethylhalicyclamine B (1), together with the known natural compound halicyclamine B (2), was isolated from the extract of the sponge Acanthostrongylophora ingens. The structure of compound 1 was determined by spectroscopic means, and it was shown that 1 is produced by reaction of 2 with CH₂Cl₂ used for extraction. Compound 1 was a selective CK1δ/ε inhibitor with an IC₅₀ of 6 μM, while the natural compound 2 was inactive. The absolute configuration of 1 was determined by quantum mechanical calculation of its ECD spectrum, and this also determined the previously unknown absolute configuration of the parent halicyclamine B (2). Computational studies, validated by NOESY data, showed that compound 1 can efficiently interact with the ATP-binding site of CK1δ in spite of its globular structure, very different from the planar structure of known inhibitors of CK1δ. This opens the way to the design of a new structural type of CK1δ/ε inhibitors.