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

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 I is produced by reaction of 2 with CH2Cl2 used for extraction. Compound 1 was a selective CK1 delta/epsilon inhibitor with an IC50 of 6 mu M, 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 CK1 delta in spite of its globular structure, very different from the planar structure of known inhibitors of CK1 delta. This opens the way to the design of a new structural type of CK1 delta/epsilon inhibitors.