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Leucettines, a Class of Potent Inhibitors of cdc2-Like Kinases and Dual Specificity, Tyrosine Phosphorylation Regulated Kinases Derived from the Marine Sponge Leucettamine B: Modulation of Alternative Pre-RNA Splicing

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Université de Rennes 1, Sciences Chimiques de Rennes, UMR CNRS 6226, Groupe ‘Ingénierie Chimique & Molécules pour le Vivant’ (ICMV), Bât. 10A, Campus de Beaulieu, Avenue du Général Leclerc, CS 74205, 35042 Rennes cedex, France
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, Oxford University, Old Road Campus Research Building, Headington, Oxford OX3 7DQ, U.K.
§ Station Biologique de Roscoff, CNRS, ‘Protein Phosphorylation and Human Disease’ Group, Place G. Teissier, BP 74, 29682 Roscoff, France
Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
# Charité-Universitätsmedizin-Berlin, Campus B. Franklin, Centrum für Herz- und Kreislaufmedizin, Hindenburgdamm 30, 12203 Berlin, Germany
(L.M. (biology)) Tel: +33.(0)2.98.29.23.39. Fax: +33.5(0)2.98.29.25.26 E-mail: [email protected]. (F.C. (chemistry)) E-mail: [email protected]. Tel: +33.(0)2.23.23.57.34. Fax: 33.(0)2.99.28.69.55 (J.P.B. (chemistry)) Tel: +33.(0)2.23.23.66.03. Fax: 33.(0)2.23.23.63.74. E-mail: [email protected]
Cite this: J. Med. Chem. 2011, 54, 12, 4172–4186
Publication Date (Web):May 26, 2011
https://doi.org/10.1021/jm200274d
Copyright © 2011 American Chemical Society

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    Abstract

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    We here report on the synthesis, optimization, and biological characterization of leucettines, a family of kinase inhibitors derived from the marine sponge leucettamine B. Stepwise synthesis of analogues starting from the natural structure, guided by activity testing on eight purified kinases, led to highly potent inhibitors of CLKs and DYRKs, two families of kinases involved in alternative pre-mRNA splicing and Alzheimer’s disease/Down syndrome. Leucettine L41 was cocrystallized with CLK3. It interacts with key residues located within the ATP-binding pocket of the kinase. Leucettine L41 inhibits the phosphorylation of serine/arginine-rich proteins (SRp), a family of proteins regulating pre-RNA splicing. Indeed leucettine L41 was demonstrated to modulate alternative pre-mRNA splicing, in a cell-based reporting system. Leucettines should be further explored as pharmacological tools to study and modulate pre-RNA splicing. Leucettines may also be investigated as potential therapeutic drugs in Alzheimer’s disease (AD) and in diseases involving abnormal pre-mRNA splicing.

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    General experimental methods and characterization data (1H and 13C NMR, HRMS, and elemental analysis) for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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