title: Synthesis and biological evaluation of novel heterocyclic quinones as inhibitors of the dual specificity protein phosphatase CDC25C.
abstract: A focused set of heterocyclic quinones based on the benzothiazole, benzoxazole, benzimidazole, indazole and isoindole was prepared and screened with respect to the inhibition of the phosphatase activity of CDC25C. Benzoxazole- and benzothiazole-diones were at least 50 times more potent in inhibiting CDC25C than their benzimidazole-indazole- or isoindole-dione counterparts. These in vitro activities were in good correlation with the anti-proliferative effects observed with Mia PaCa-2 and DU-145 human tumor cell cultures. The IC(50) values obtained by WST-1 colorimetric assay ranged from 0.10 to 0.50 microM for the benzoxazole- or benzothiazole-diones and were above 10 microM for the other heterocyclic diones. This study further illustrates how the activity of the quinone pharmacophore can be selectively modulated by changing the type of five-membered heterocycle fused to the quinone ring.
authors.affiliation: Ipsen Research Laboratories, Institut Henri Beaufour, 5 avenue du Canada, 91960 Les Ulis, France. olivier.lavergne@ipsen.com
authors.forename: Olivier
authors.initials: O
authors.lastname: Lavergne
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Fernandes
authors.forename: Laetitia
authors.initials: L
authors.lastname: Bréhu
authors.forename: Alban
authors.initials: A
authors.lastname: Sidhu
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Brézak
authors.forename: Grégoire
authors.initials: G
authors.lastname: Prévost
authors.forename: Bernard
authors.initials: B
authors.lastname: Ducommun
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Contour-Galcera
mesh_terms: D052160:Benzothiazoles / Q000737:chemistry; D001583:Benzoxazoles / Q000737:chemistry; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003124:Colorimetry; D015195:Drug Design; D005029:Ethylenediamines / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D011809:Quinones / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013696:Temperature; D013997:Time Factors; D020687:cdc25 Phosphatases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D001583:Benzoxazoles; D018797:Cell Cycle Proteins; D005029:Ethylenediamines; D011809:Quinones; D011994:Recombinant Proteins; C027450:dimethylethylenediamine; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases