RESUMO
CDC25 phosphatases are key cell cycle regulators and represent very attractive but challenging targets for anticancer drug discovery. Here, we explored whether fragment-based screening represents a valid approach to identify inhibitors of CDC25B. This resulted in identification of 2-fluoro-4-hydroxybenzonitrile, which directly binds to the catalytic domain of CDC25B. Interestingly, NMR data and the crystal structure demonstrate that this compound binds to the pocket distant from the active site and adjacent to the protein-protein interaction interface with CDK2/Cyclin A substrate. Furthermore, we developed a more potent analogue that disrupts CDC25B interaction with CDK2/Cyclin A and inhibits dephosphorylation of CDK2. Based on these studies, we provide a proof of concept that targeting CDC25 phosphatases by inhibiting their protein-protein interactions with CDK2/Cyclin A substrate represents a novel, viable opportunity to target this important class of enzymes.
Assuntos
Fosfatases cdc25/antagonistas & inibidores , Sítios de Ligação , Cristalização , Ciclina A/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Inibidores Enzimáticos , Escherichia coli , Regulação Bacteriana da Expressão Gênica/fisiologia , Regulação Enzimológica da Expressão Gênica , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Ligação Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Bibliotecas de Moléculas Pequenas , Fosfatases cdc25/química , Fosfatases cdc25/metabolismoRESUMO
Reaction of 6-arylamino-1,3-dialkyluracils with anhydrides of polyfluorocarboxylic acids in the presence of pyridine and subsequent cyclization with concentrated H2SO4 gave the corresponding 1,3-dialkyl-5-(polyfluoroalkyl)pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones (5-polyfluoroalkyl-5-deazaalloxazines). The reactivity of these compounds towards nucleophilic reagents, such as sodium cyanoborohydride, acetophenone, nitromethane, potassium cyanide, indole and p-thiocresol, as well as Suzuki and Sonogashira couplings are described. The nucleophilic addition takes place at the 5-position of the 5-deazaalloxazine system and is in many cases irreversible to give 5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-dione derivatives in good to excellent yields.
Assuntos
Compostos Aza/síntese química , Flavinas/síntese química , Quinolinas/síntese química , Alquilação , Compostos Aza/química , Ciclização , Flavinas/química , Halogenação , Piridinas/química , Quinolinas/química , Uracila/análogos & derivadosRESUMO
A facile synthetic approach for the synthesis of 1,8-naphthyridine-4(1H)-one derivatives via a catalyst free and Pd-supported tandem amination sequence is developed and described. In a case of aliphatic amines reaction proceeds in a catalyst free mode, however anilines demand Pd-supported reaction conditions.
Assuntos
Alcinos/química , Aminas/química , Cetonas/química , Naftiridinas/síntese química , Piridinas/química , Aminação , Catálise , Ciclização , Espectroscopia de Ressonância Magnética , Paládio/químicaRESUMO
The first synthesis of 3-methoxalylchromone was described. The reaction of the latter with electron-rich aminoheterocycles afforded a set of heteroannelated pyridines bearing a CO(2)Me substituent located at the α-position of the pyridine core.
