RESUMO
This present study identifies a number of azolyl-substituted indoles as potent inhibitors of aromatase. In the sub-series of 3-(azolylmethyl)-1H-indoles, four imidazole derivatives and their triazole analogues were tested. Imidazole derivatives 11 and 14 in which the benzyl moiety was substituted by 2-chloro and 4-cyano groups, respectively, were the most active, with IC50 values ranging between 0.054 and 0.050 microM. In the other sub-series, eight 3-(alpha-azolylbenzyl)-1H-indoles were prepared and tested. Compound 30, the N-ethyl imidazole derivative, proved to be an aromatase inhibitor, showing an IC50 value of 0.052 microM. All target compounds were further evaluated against 17alpha-hydroxylase/C17,20-lyase to determine their selectivity profile.
Assuntos
Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacologia , Azóis/química , Indóis/síntese química , Indóis/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Animais , Inibidores da Aromatase/química , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Indóis/química , Concentração Inibidora 50 , Masculino , Microssomos/química , Microssomos/efeitos dos fármacos , Estrutura Molecular , Placenta/enzimologia , Ratos , Relação Estrutura-Atividade , Testículo/enzimologiaRESUMO
A three-dimensional (3-D) structure of human aromatase (CYP 19) was modeled on the basis of the crystal structure of rabbit CYP2C5, the first solved X-ray structure of an eukaryotic cytochrome P450 and was evaluated by docking S-fadrozole and the steroidal competitive inhibitor (19R)-10-thiiranylestr-4-ene-3,17-dione, into the enzyme active site. According to a previous pharmacophoric hypothesis described in the literature, the cyano group of S-fadrozole partially mimics the steroid backbone C(17) carbonyl group of (19R)-10-thiiranylestr-4-ene-3,17-dione, and was oriented in a favorable position for H-bonding with the newly identified positively charged residues Lys 119 and Arg435. In addition, this model is consistent with the recent combined mutagenesis/modeling studies already published concerning the roles ofAsp309 and His480 in the aromatization of the steroid A ring.
Assuntos
Aromatase/química , Estrenos/química , Fadrozol/química , Modelos Moleculares , Sequência de Aminoácidos , Animais , Aromatase/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Ligação Competitiva , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrenos/farmacologia , Fadrozol/farmacologia , Humanos , Ligação de Hidrogênio , Dados de Sequência Molecular , Estrutura Molecular , Coelhos , Alinhamento de Sequência , Relação Estrutura-AtividadeRESUMO
Aromatase (P450 arom) is a target of pharmacological interest for the treatment of breast cancer. New series of 7-(alpha-azolylbenzyl)-1H-indoles and indolines were synthesized as non-steroidal inhibitors of P450 arom. Selectivity was studied towards P450 17alpha enzyme. The most active compound, 1-ethyl-7-[(imidazol-1-yl)(4-chlorophenyl)methyl]-1H-indole 12c exhibited promising relative potency (rp) of 336 (rp of aminoglutethimide=1) and most of the described azoles were active and selective towards P450 arom.
