RESUMO
Since many estrogen derivatives exhibit anti-hormone or enzyme inhibition potential, a large number of steroidal derivatives have been synthesised from appropriate precursors, in order to obtain potential therapeutics for the treatment of hormone-dependent cancers. In molecular docking studies, based on X-ray crystallographic analysis, selected D-homo and D-seco estratriene derivatives were predicted to bind strongly to estrogen receptor α (ERα), aromatase and 17,20 lyase, suggesting they could be good starting compounds for antihormonal studies. Test results in vivo suggest that these compounds do not possess estrogenic activity, while some of them showed weak anti-estrogenic properties. In vitro anti-aromatase and anti-lyase assays showed partial inhibition of these two enzymes, while some compounds activated aromatase. Aromatase activators are capable of promoting estrogen synthesis for treatment of pathological conditions caused by estrogen depletion, e.g. osteopenia or osteoporosis.
Assuntos
Aromatase/metabolismo , Inibidores Enzimáticos/farmacologia , Estrenos/farmacologia , Homosteroides/farmacologia , Antagonistas de Hormônios/farmacologia , Secoesteroides/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrenos/síntese química , Estrenos/química , Estrogênios/biossíntese , Feminino , Homosteroides/síntese química , Homosteroides/química , Antagonistas de Hormônios/síntese química , Antagonistas de Hormônios/química , Modelos Moleculares , Conformação Molecular , Ratos , Ratos Wistar , Secoesteroides/síntese química , Secoesteroides/química , Estereoisomerismo , Esteroide 17-alfa-Hidroxilase/metabolismo , Relação Estrutura-AtividadeRESUMO
The starting compound for synthesis of new 16,17-seco-estratriene derivatives was 3-benzyloxy-17-hydroxy-16,17-secoestra-1,3,5(10)-triene-16-nitrile (1b), obtained from estrone in several synthetic steps. 17-Tosyl, -chloro-, bromo-, and -iodo- derivatives 2b, 4b, 5b, and 6b were prepared directly from secocyanoalcohol 1b, while the 17-fluoro-derivative 3b was obtained from tosylate 2b in the reaction with tetrabutyl ammonium fluoride. The corresponding 3-hydroxy derivatives of these compounds were produced by action of hydrogen in presence of Pd/C, except the 3-hydroxy-17-iodo derivative 6a, which was obtained from 3-hydroxy-17-tosyloxy derivative 2a. All the newly synthesized compounds in biological tests on experimental animals exhibited an almost total loss of estrogenic activity, while most of them even prevented the action of endogenous estrogens. On the other hand, most of them, except compounds 3a and 6b, partially hindered the action of estradiol benzoate, behaving as moderate antagonists.
