title: Chloromethylhalicyclamine B, a Marine-Derived Protein Kinase CK1δ/ε Inhibitor.
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 CH2Cl2used for extraction. Compound 1 was a selective CK1δ/ε inhibitor with an IC50of 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.
authors.affiliation: Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle , 57 Rue Cuvier (C.P. 54), 75005 Paris, France.
authors.forename: Germana
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle , 57 Rue Cuvier (C.P. 54), 75005 Paris, France.
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Bourguet-Kondracki
authors.affiliation: Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle , 57 Rue Cuvier (C.P. 54), 75005 Paris, France.
authors.forename: Linh H
authors.initials: LH
authors.lastname: Mai
authors.affiliation: Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle , 57 Rue Cuvier (C.P. 54), 75005 Paris, France.
authors.forename: Arlette
authors.initials: A
authors.lastname: Longeon
authors.affiliation: The NeaNat Group, Dipartimento di Farmacia, Università degli Studi di Napoli Federico II , Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Teta
authors.affiliation: ManRos Therapeutics, Perharidy Research Center , 29680 Roscoff, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Naturalis Biodiversity Center , P.O. Box 9517, 2300 RA Leiden, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Van Soest
authors.affiliation: The NeaNat Group, Dipartimento di Farmacia, Università degli Studi di Napoli Federico II , Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Mangoni
authors.affiliation: The NeaNat Group, Dipartimento di Farmacia, Università degli Studi di Napoli Federico II , Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Costantino
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors / Q000302:isolation & purification*; D007214:Indonesia; D008386:Marine Biology; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009792:Oceans and Seas; D011161:Porifera / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000620038:chloromethylhalicyclamine B; D048148:Casein Kinase Idelta