RESUMO
Herein we describe concise enantioselective chemical syntheses of (-)-viridin and (-)-viridiol. Our convergent approach couples two achiral fragments of similar complexity and employs an enantioselective intramolecular Heck reaction to set the absolute stereochemical configuration of an all-carbon quaternary stereocenter. To complete the syntheses of these base- and nucleophile-sensitive natural products, we conduct carefully orchestrated site- and diastereoselective oxidations and other transformations. Our work is the first to generate these targets as single enantiomers.
Assuntos
Androstenodióis/síntese química , Androstenos/síntese química , Bacteriocinas/síntese química , Androstenodióis/química , Androstenos/química , Bacteriocinas/química , Estrutura Molecular , EstereoisomerismoRESUMO
Taking into consideration the structural requirements for cytotoxicity and aromatase inhibition, several new 16E-arylidenosteroidal derivatives have been prepared and evaluated for their cytotoxic and aromatase inhibitory activity. The new steroidal analogues 3, 5-8 and 11 exhibited significant cytotoxic effects when screened against three cancer cell lines, MCF-7 (breast), NCl-H460 (lung) and SF-268 central nervous system (CNS) at 100 µM and sensible cytotoxic effects subsequently in sixty cancer cell lines derived from nine cancers types (leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers). The imidazolyl substituted steroidal derivatives 5 and 7 exhibited strong inhibition of the aromatase enzyme with 16-[4-{3-(imidazol-1-yl)propoxy}-3-methoxybenzylidene]-5-androstene-3ß,17ß-diol (7) displaying 13 times more potency in comparison to aminoglutethimide.
Assuntos
Androstenodióis/síntese química , Androstenodiona/análogos & derivados , Antineoplásicos/síntese química , Inibidores da Aromatase/síntese química , Aromatase/química , Esteroides/química , Androstenodióis/química , Androstenodióis/toxicidade , Androstenodiona/síntese química , Androstenodiona/química , Androstenodiona/toxicidade , Antineoplásicos/química , Antineoplásicos/toxicidade , Aromatase/metabolismo , Inibidores da Aromatase/química , Inibidores da Aromatase/toxicidade , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Esteroides/síntese química , Esteroides/toxicidadeRESUMO
As part of our investigation into the structure-activity relationship of a novel class of aromatase inhibitors, C(19) steroids having no oxygen function at C-3, we tested aromatase inhibition activity of polar diol compounds 4,19-dihydroxyandrost-5-en-17-ones (25 and 27) and 6,19-dihydroxyandrost-4-en-17-ones (36 and 37). 4alpha,19-Diol 25 was synthesized from tert-butyldimethylsilyoxyandrost-4-ene steroid (9) through its OsO(4) oxidation, giving the 4alpha,5alpha-dihydroxy derivative 12, as a key reaction. Acetylation of 5beta,6alpha-dihydroxy-19-acetate 30 and its 5alpha,6beta-analogue 31 followed by dehydration with SOCl(2) and alkaline hydroxysis gave 6alpha,19-diol 36 and its 6beta-isomer 37, respectively. The stereochemistry of a hydroxy group at C-4 of compound 25 and that at C-6 of compounds 36 and 37 were determined on the basis of (1)H NMR spectroscopy in each case. 4beta,19-Diol 27, previously synthesized, was identified as an extremely powerful competitive inhibitor of aromatase (K(i) = 3.4 nM). In contrast, its 4alpha,19-dihydroxy isomer 25 and other series of diol compounds, 6,19-dihydroxy-4-en-17-one steroids, were moderate to poor competitive inhibitors (K(i) = 110-800 nM). Through this series of analyses, it was concluded that hydrophilic interaction of a 4beta,19-diol function with the active site of aromatase plays a critical role in the tight binding of 3-deoxy-5-ene steroids.
Assuntos
Androstenodióis/síntese química , Aromatase/metabolismo , Inibidores Enzimáticos/síntese química , Androstenodióis/química , Androstenodióis/metabolismo , Androstenodióis/farmacologia , Inibidores da Aromatase , Sítios de Ligação , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Hidroxilação , Técnicas In Vitro , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Placenta/enzimologia , Placenta/ultraestrutura , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Two methods to produce the 17-cyanohydrin, using potassium cyanide in acetic acid/methanol or acetone cyanohydrin with aqueous sodium hydroxide, were followed with 9 alpha-hydroxyandrost-4-ene-3,17-dione, both providing 17 beta-cyano-9 alpha,17 alpha-dihydroxyandrost-4-en-3-one. The selectivity of one of these methods, that which uses acetone cyanohydrin, is not in agreement with a comparable reaction with the 9 alpha-unsubstituted androst-4-ene-13,17-dione to give the 17 alpha-cyano-17 beta-hydroxy product, as reported in the literature and confirmed by us. The 9 alpha-hydroxy and 17 alpha-hydroxy groups were used for the regioselective introduction of 9(11)- and 16(17)-double bonds by dehydrating 17 beta-cyano-9 alpha,17 alpha-dihydroxyandrost-4-en-3-one under different conditions.
Assuntos
Androstenodióis/síntese química , Fenômenos Químicos , Química , Espectroscopia de Ressonância Magnética , ÁguaRESUMO
Alkaline hydrolysis of a 16beta-acetoxy-17-oxo steroid is accompanied by almost complete rearrangement of the product to a 16-oxo-17beta-hydroxy steroid. Hydrolysis can be achieved without rearrangement by 1) formation of a C-17 semicarbazone, 2) alkaline removal of the acetate group, and 3) removal of the semicarbazone group in the presence of pyruvic acid-acetic acid. By employing this technique, the title compound was obtained from its diacetate in a yield of 65%.
Assuntos
Androstenodióis/síntese química , Fenômenos Químicos , Química , Cromatografia em Camada Fina , Hidrólise , Espectroscopia de Ressonância Magnética , Semicarbazonas/síntese químicaRESUMO
A series of bridged androstenediol derivatives was prepared. The bridged compounds exhibited reduced ER-beta selectivity relative to uncyclized analogs.
Assuntos
Androstenodióis/síntese química , Receptor beta de Estrogênio/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Androstenodióis/farmacologia , Ciclização , Receptor beta de Estrogênio/química , Receptor beta de Estrogênio/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The principal urinary metabolites of 2-formyl-17alpha-methylandrosta-1,4-diene-11alpha,17beta-dihydroxy-3-one (for myldienolone) are 2-carboxy- and 2-hydroxymethyl-17 alpha-methylandrosta-11alpha,17beta-dihydroxy-3-one, whose structures were confirmed by comparing them with synthesized samples.