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.
Chloromethylhalicyclamine B, a Marine-Derived Protein Kinase CK1δ/ε Inhibitor / Esposito, Germana; Marie Lise, Bourguet Kondracki; Linh H, Mai; Arlette, Longeon; Teta, Roberta; Laurent, Meijer; Rob, Van Soest; Mangoni, Alfonso; Costantino, Valeria. - In: JOURNAL OF NATURAL PRODUCTS. - ISSN 0163-3864. - 79:(2016), pp. 2953-2960. [10.1021/acs.jnatprod.6b00939]
Chloromethylhalicyclamine B, a Marine-Derived Protein Kinase CK1δ/ε Inhibitor
ESPOSITO, GERMANA;TETA, ROBERTA;MANGONI, ALFONSO;COSTANTINO, VALERIA
2016
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
