RESUMO
Syntheses of novel heterocyclic derivatives of 18-nor-equilenin, namely, (12H-11-oxa-17-thia-15-aza-cyclopenta[a]phenanthrene-16-yl)-hydrazine (4a/b) and its fused [1,2,4]triazolo derivatives6H-5-oxa-7-thia-8,9,10a-triaza-pentaleno[4,5-a]phenanthrene (5a/b), 10-methyl-6H-5-oxa-7-thia-8,9,10a-triaza-pentaleno[4,5-a]phenanthrene (6a/b) and tetrazolo derivatives 1-substituted-6H-5-oxa-7-thia-8,9,10,10a-tetraaza-pentaleno[4,5-a]phenanthrene (7a/b) along with their antibacterial activities are reported.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Equilenina/síntese química , Equilenina/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Antibacterianos/química , Bacillus subtilis/efeitos dos fármacos , Equilenina/química , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura MolecularRESUMO
4-Methoxyequilin and 2-methoxyequilin were synthesized from the corresponding 4-bromoequilin and 2-iodoequilin derivatives, respectively, by nucleophilic displacement of halogen with methoxide ion in the presence of copper (II) chloride and 15-crown-5-ether. 4-Bromoequilin was prepared by reacting equilin with one equivalent of N-bromoacetamide. 2-Iodoequilin was prepared by reductive dehalogenation of 2,4-diiodoequilin, which in turn was obtained by treatment of equilin with two equivalents of iodine in methanolic ammonium hydroxide solution. 4-Methoxy-equilenin and 2-methoxyequilenin were prepared from the corresponding 4-iodo- and 2-iodo-7 epsilon, 8 epsilon-epoxyestrone derivatives, respectively. Nucleophilic displacement of iodine with methoxide ion was carried out as described earlier with simultaneous aromatization of the B ring leading to 4- and 2-methoxyequilenin derivatives. Alternatively, 4-methoxyequilenin was obtained from 4-methoxyequilin by selenium dioxide oxidation.
Assuntos
Estrogênios/síntese química , Animais , Equilenina/análogos & derivados , Equilenina/síntese química , Equilina/análogos & derivados , Equilina/síntese química , CavalosRESUMO
4-Hydroxyequilin, 4-hydroxyequilenin, and 16 alpha-hydroxyequilenin were synthesized as authentic specimens for the metabolic studies of equine estrogens. The synthetic route leading to the 4-hydroxylated compounds was started from o-vanillin, which was transformed into the beta-ketosulfoxide (2b) by sequential multistep reactions. This was converted to the alpha,beta-unsaturated ketone (3) as Michael acceptor. Condensation of 3 with 2-methylcyclopentane-1,3-dione, followed by ring closure with methanesulfonic acid provided the cyclized estrapentaene (5). Several oxidoreduction reactions were then performed to give the desired compounds. Preparation of 16 alpha-hydroxyequilenin was attained by reductive cleavage of the 16 alpha,17 alpha-epoxide formed from equilenin.
Assuntos
17-Cetosteroides/síntese química , Equilenina , Equilenina/síntese química , Equilina , Equilina/síntese química , Benzaldeídos , Fenômenos Químicos , Química , Equilenina/análogos & derivados , Equilina/análogos & derivados , Hidroxilação , Estrutura Molecular , OxirreduçãoRESUMO
Equilin and equilenin make up approximately 20% of Premarin which is currently the most popular estrogen replacement therapy. Although there are numerous health benefits of estrogen replacement therapy, there are concerns over the link between estrogen replacement therapy and breast and endometrial cancer risk. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols which are further oxidized to electrophilic/redox active o-quinones which have the potential to both initiate and promote the carcinogenic process. In this investigation, we have synthesized potential metabolites of equilin and equilenin, 2-hydroxyequilin and 2-hydroxyequilenin, respectively, as well as their methyl ether metabolites. These compounds were synthesized from commercially available optically pure equilin via a practical and efficient approach; five steps gave 2-methoxyequilin from which 2-hydroxyequilin was prepared by BBr3-catalyzed demethylation in one step. Similarly, treating 2-methoxyequilin with SeO2 followed by demethylation with BBr3 produced 2-hydroxyequilenin. The structures of the catechols as well as those of their methoxy ethers were unambiguously characterized by one-dimensional and two-dimensional NMR experiments, including 1H, 13C, APT, COSY, HMBC, and HMQC as well as mass spectrometry.