RESUMEN
Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC(50) = 30 nM), several additional analogues were prepared. Optimization of the C-4 anilino group of 1a led to 1c, which contains a 2,4-dichloro-5-methoxy-substituted aniline. Replacement of the methoxy group at C-7 of 1c with a 3-(morpholin-4-yl)propoxy group provided 2c, resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c with other trisubstituted anilines at C-4 were also potent Src inhibitors, and the propoxy group of 2c was preferred over ethoxy, butoxy, or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a, which had an IC(50) of 1.2 nM in the Src enzymatic assay, an IC(50) of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a, which had higher 1 and 4 h plasma levels than 2c, effectively inhibited tumor growth in xenograft models.
Asunto(s)
Antineoplásicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Nitrilos/síntesis química , Piperazinas/síntesis química , Quinolinas/síntesis química , Familia-src Quinasas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Línea Celular Transformada , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Femenino , Fibroblastos/metabolismo , Humanos , Immunoblotting , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nitrilos/química , Nitrilos/farmacocinética , Nitrilos/farmacología , Fosforilación , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacología , Quinolinas/química , Quinolinas/farmacocinética , Quinolinas/farmacología , Relación Estructura-Actividad , Células Tumorales Cultivadas , Tirosina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To determine the presence or absence of claims for the clinical art of chiropractic that are not currently justified by available scientific evidence or are intrinsically untestable. DESIGN: A survey of patient education and promotional material produced by national, state, and provincial societies and research agencies in Canada and the United States. METHOD: Patient brochures were solicited from the 3 largest provincial, 3 largest state, and the 3 largest national professional associations in the United States and Canada. Similar requests were made of 2 research agencies supported by the national associations. Brochures were reviewed for the presence or absence of unsubstantiated claims. RESULTS: Of the 11 organizations sampled, 9 distribute patient brochures. Of these 9 organizations, all distribute patient brochures that make claims for chiropractic services that have not been scientifically validated. CONCLUSION: The largest professional associations in the United States and Canada distribute patient brochures that make claims for the clinical art of chiropractic that are not currently justified by available scientific evidence or that are intrinsically untestable. These assertions are self-defeating because they reinforce an image of the chiropractic profession as functioning outside the boundaries of scientific behavior.