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J Med Chem ; 53(24): 8734-46, 2010 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-21080724

RESUMEN

We have shown previously that the target of the potent cytotoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridylmethylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C² of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays.


Asunto(s)
Antineoplásicos/síntesis química , Benzamidas/síntesis química , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Quinazolinas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Benzamidas/química , Benzamidas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Modelos Moleculares , Quinazolinas/química , Quinazolinas/farmacología , Relación Estructura-Actividad
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