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 1 is produced by reaction of 2 with CH 2 Cl 2 used for extraction. Compound 1 was a selective CK1δ/ε inhibitor with an IC 50 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.