RESUMO
Based on biological properties of epoxyquinols from natural sources, bromo and epoxyquinols derived from estrone were synthesized and screened against Fem-X, HeLa and K(562) cell lines. Evidence was found that the bromine atom and the epoxy moiety significantly increase the antiproliferative activity within the series.
Assuntos
Antineoplásicos/síntese química , Bromo/química , Compostos de Epóxi/química , Estrona/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estrona/química , Estrona/farmacologia , Células HeLa , Humanos , Células K562 , Células Tumorais CultivadasRESUMO
Cholic acid-derived 1,2,4,5-tetraoxanes were synthesized in order to explore the influence of steroid carrier on its antimalarial and antiproliferative activity in vitro. Starting with chiral ketones, cis and trans series of diastereomeric tetraoxanes were obtained, and the cis series was found to be approximately 2 times as active as the trans against Plasmodium falciparum D6 and W2 clones. The same tendency was observed against human melanoma (Fem-X) and human cervix carcinoma (HeLa) cell lines. The amide C(24) termini, for the first time introduced into the carrier molecule of a tetraoxane pharmacophore, significantly enhanced both antimalarial and antiproliferative activity, as compared to the corresponding methyl esters, with cis-bis(N-propylamide) being most efficient against the chloroquine-susceptible D6 clone (IC(50) = 9.29 nM). cis- and trans-bis(N-propylamides) were also screened against PBMC, and PHA-stimulated PBMC, showing a cytotoxicity/antimalarial potency ratio of 1/10 000.
Assuntos
Antimaláricos/síntese química , Antineoplásicos/síntese química , Ácidos Cólicos/síntese química , Compostos de Espiro/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Ácidos Cólicos/química , Ácidos Cólicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Plasmodium falciparum/efeitos dos fármacos , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The synthesis of delta 7,9(11)-lanostadiene derivatives functionalized at C(32) starting from 3 beta-acetoxy-7 alpha,32-epoxylanostan-11-one has been presented. The delta 7,9(11) moiety was efficiently introduced in three steps in 71% yield by the regioselective abstraction of allylic 8 beta hydrogen. The formyl group of the key intermediate, 3 beta-benzoyloxylanosta-7,9(11)-dien-32-al, has been stereoselectively alkylated into (32S) derivative, whereas its oxidation unexpectedly afforded 3 beta-benzoyloxy-7-oxolanost-8-ene-32,11 alpha-lactone and not the corresponding acid. delta 7,9(11)-lanostadienes possessing HC(32)=O, C(32) [symbol: see text] N, HC(32S)CH3OH, H2C(32)OH, as well as some 11-keto lanostenes, were tested in vitro against several purified cholesterogenic enzymes showing moderate activity, with most the active aldehyde 16 having IC50 = 86 microM.
Assuntos
Anticolesterolemiantes/síntese química , Inibidores Enzimáticos/síntese química , Lanosterol/análogos & derivados , Lanosterol/metabolismo , Animais , Cristalografia por Raios X , Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lanosterol/síntese química , Lanosterol/farmacologia , Masculino , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Oxirredutases/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Esterol 14-DesmetilaseRESUMO
Cholestane-derived gem-dihydroperoxides and tetraoxanes were synthesized starting from 5 alpha- and 5 beta-cholestan-3-ones by acid-catalyzed addition of hydrogen peroxide to the ketone. They were characterized by IR, NMR, and mass spectroscopy analysis aided by molecular mechanics calculations, and, in the instance of 5 beta-cholestane-3 alpha,3 beta-dihydroperoxide (6), by x-ray analysis. The synthesized compounds were tested in vitro against Plasmodium falciparum Sierra Leone (D6) and Indochina (W2) malaria clones. All compounds were inactive to both clones, with the exception of tetraoxane 7a, which exhibited modest activity toward D6 clone with IC50 = 155 nM.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Colestanos/química , Colestanos/síntese química , Peróxidos/química , Animais , Antimaláricos/síntese química , Colestanos/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Estrutura Molecular , Peróxidos/síntese química , Peróxidos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Esteroides/químicaRESUMO
The two-phase oxidation of steroidal 5-en-3 beta-ol (via 5-en-3-ones) into corresponding 4-en-3,6-diones in diethyl ether with Jones reagent was investigated. It was found that the system Jones reagent/diethyl ether enables short reaction times and easy isolation of the obtained products. The exclusive abstraction of 4 alpha-hydrogen during oxidation, together with molecular mechanics (MM2), and semiempirical (PM3) calculations, suggest that boat conformation of ring A precedes the formation of corresponding radicals (or cations).