Chloromethylhalicyclamine B, a Marine-Derived Protein Kinase CK1δ/ε Inhibitor.
J Nat Prod
; 79(11): 2953-2960, 2016 11 23.
Article
em En
| MEDLINE
| ID: mdl-27933894
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.
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Base de dados:
MEDLINE
Assunto principal:
Poríferos
/
Pirimidinas
/
Compostos Bicíclicos Heterocíclicos com Pontes
/
Caseína Quinase Idelta
/
Inibidores de Proteínas Quinases
/
Alcaloides
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article