RESUMEN
The irreversible aromatase inhibitor exemestane (6) reacts with nitromethane and sodium ethanolate to yield the Michael adduct 9. The aldehyde 10 is obtained by Nef reaction of the nitro compound 9 and affords the 1,4-dihydropyridine (DHP) 11 by Hantzsch reaction using methyl beta-aminocrotonate in acetic acid. The new compounds showed a reduced inhibitory potency towards aromatase (IC50 values: 9, 0.91 microM; 10, 2.5 microM; 11, 10 microM) compared to 6 (IC50 = 0.23 microM). The 1,4-DHP 11 was dehydrogenated with CAN or electrochemically (E1/2 =1.18 V) to yield the corresponding pyridine 12.
Asunto(s)
Androstadienos/síntesis química , Androstadienos/farmacología , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/farmacología , Cristalografía por Rayos X , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Microsomas/efectos de los fármacos , Microsomas/enzimología , Modelos Moleculares , Conformación Molecular , Oxidación-Reducción , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Reaction of androsta-1,4-diene-3,17-dione (1) with pyrrolidine and p-toluenesulfonic acid in toluene gives 3-pyrrolidino-estra-1,3,5(10)-triene-6,17-dione (7) in poor yield, whose structure is shown by X-ray analysis. Compared with 3H-estradiol, compound 7 shows only a weak receptor binding activity tested in an in vitro screening using rabbit uterus cytosol.
