title: Design and synthesis of novel bis-thiazolone derivatives as micromolar CDC25 phosphatase inhibitors: effect of dimerisation on phosphatase inhibition.
abstract: CDC25 phosphatases are involved in deregulated cell cycle progression and tumor development with poor prognosis. Among the most potent CDC25 inhibitors, quinonoid-based derivatives have been extensively studied. Dimerisation of heterocyclic quinones has led to IRC-083864, a bis-quinone compound with increased CDC25B inhibitory activity. Thirty-one bis-thiazolone derivatives were synthesized and assayed for CDC25 inhibitory activity. Most of the dimers displayed enhanced inhibitory activities with micromolar IC(50) values lower than that observed for each thiazolone scaffold separately. Moreover, most of these compounds were selective CDC25 inhibitors. Dimer 40 showed an IC(50) value of 2.9 μM and could inhibit CDC25 activity without generating reactive oxygen species which is likely to occur with quinone-based inhibitors. Molecular docking studies suggested that the dimers could bind simultaneously to the active site and the inhibitor binding pocket.
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, PRES Paris cité, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors.forename: Manal
authors.initials: M
authors.lastname: Sarkis
authors.forename: Diem Ngan
authors.initials: DN
authors.lastname: Tran
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Kolb
authors.forename: Maria A
authors.initials: MA
authors.lastname: Miteva
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Braud
mesh_terms: D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D013844:Thiazoles; D020687:cdc25 Phosphatases