RESUMO
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.
Assuntos
Androstadienos/síntese química , Androstadienos/farmacologia , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacologia , Cristalografia por Raios X , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Modelos Moleculares , Conformação Molecular , Oxirredução , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
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.