Marine-Derived 2-Aminoimidazolone Alkaloids. Leucettamine B-Related Polyandrocarpamines Inhibit Mammalian and Protozoan DYRK & CLK Kinases
Nadège Loaëc,
Eletta Attanasio,
Benoît Villiers,
Emilie Durieu,
Tania Tahtouh,
Morgane Cam,
Rohan A. Davis,
Aline Alencar,
Mélanie Roué,
Marie-Lise Bourguet-Kondracki,
Peter Proksch,
Emmanuelle Limanton,
Solène Guiheneuf,
François Carreaux,
Jean-Pierre Bazureau,
Michelle Klautau,
Laurent Meijer
Affiliations
Nadège Loaëc
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France
Eletta Attanasio
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France
Benoît Villiers
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France
Emilie Durieu
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France
Tania Tahtouh
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France
Morgane Cam
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France
Rohan A. Davis
Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
Aline Alencar
Universidade Federal do Rio de Janeiro, Instituto de Biologia—Departamento de Zoologia, Av. Carlos Chagas Filho 373-CCS-Bloco A-Sala A0-100, Ilha do Fundão, 21941-902 Rio de Janeiro, Brasil
Mélanie Roué
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
Marie-Lise Bourguet-Kondracki
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
Peter Proksch
Institut für Pharmazeutische Biologie und Biotechnologie, Universitätsstr. 1, 40225 Düsseldorf, Germany
Emmanuelle Limanton
Université de Rennes 1, Institut des Sciences Chimiques de Rennes, ISCR UMR CNRS 6226, Groupe Chimie Organique et Interfaces (CORINT), Bât. 10A, Campus de Beaulieu, Avenue du Général Leclerc, CS 74205, 35042 Rennes CEDEX, Bretagne, France
Solène Guiheneuf
Université de Rennes 1, Institut des Sciences Chimiques de Rennes, ISCR UMR CNRS 6226, Groupe Chimie Organique et Interfaces (CORINT), Bât. 10A, Campus de Beaulieu, Avenue du Général Leclerc, CS 74205, 35042 Rennes CEDEX, Bretagne, France
François Carreaux
Université de Rennes 1, Institut des Sciences Chimiques de Rennes, ISCR UMR CNRS 6226, Groupe Chimie Organique et Interfaces (CORINT), Bât. 10A, Campus de Beaulieu, Avenue du Général Leclerc, CS 74205, 35042 Rennes CEDEX, Bretagne, France
Jean-Pierre Bazureau
Université de Rennes 1, Institut des Sciences Chimiques de Rennes, ISCR UMR CNRS 6226, Groupe Chimie Organique et Interfaces (CORINT), Bât. 10A, Campus de Beaulieu, Avenue du Général Leclerc, CS 74205, 35042 Rennes CEDEX, Bretagne, France
Michelle Klautau
Universidade Federal do Rio de Janeiro, Instituto de Biologia—Departamento de Zoologia, Av. Carlos Chagas Filho 373-CCS-Bloco A-Sala A0-100, Ilha do Fundão, 21941-902 Rio de Janeiro, Brasil
Laurent Meijer
ManRos Therapeutics, Perharidy Research Center, 29680 Roscoff, Bretagne, France
A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina. The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton), physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) and potential pharmacological leads for the treatment of several diseases, including Alzheimer’s disease and Down syndrome. We assembled a small library of marine sponge- and ascidian-derived 2-aminoimidazolone alkaloids, along with several synthetic analogues, and tested them on a panel of mammalian and protozoan kinases. Polyandrocarpamines A and B were found to be potent and selective inhibitors of DYRKs and CLKs. They inhibited cyclin D1 phosphorylation on a DYRK1A phosphosite in cultured cells. 2-Aminoimidazolones thus represent a promising chemical scaffold for the design of potential therapeutic drug candidates acting as specific inhibitors of disease-relevant kinases, and possibly other disease-relevant targets.