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1.
Mar Drugs ; 10(6): 1383-90, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22822379

RESUMO

Chalinulasterol (1) a new chlorinated sterol disulfate was isolated from the Caribbean sponge Chalinula molitba. Its structure was elucidated using mass spectrometry and NMR experiments. The possible role of chalinulasterol as modulator of the PXR nuclear receptor was investigated but, in spite of the close structural relationship with the PXR agonist solomonsterol A (2), it showed no activity. The structural requirements for the PXR nuclear receptor activity were discussed.


Assuntos
Poríferos/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Esteroides Clorados/química , Esteroides Clorados/farmacologia , Animais , Região do Caribe , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Receptor de Pregnano X , Esteroides Clorados/isolamento & purificação
2.
J Steroid Biochem Mol Biol ; 128(1-2): 38-50, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22001566

RESUMO

The human steroidogenic cytochromes P450 CYP17A1 (P450c17, 17α-hydroxylase/17,20-lyase) and CYP21A2 (P450c21, 21-hydroxylase) are required for the biosynthesis of androgens, glucocorticoids, and mineralocorticoids. Both enzymes hydroxylate progesterone at adjacent, distal carbon atoms and show limited tolerance for substrate modification. Halogenated substrate analogs have been employed for many years to probe cytochrome P450 catalysis and to block sites of reactivity, particularly for potential drugs. Consequently, we developed efficient synthetic approaches to introducing one or more halogen atom to the 17- and 21-positions of progesterone and pregnenolone. In particular, novel 21,21,21-tribromoprogesterone and 21,21,21-trichloroprogesterone were synthesized using the nucleophilic addition of either bromoform or chloroform anion onto an aldehyde precursor as the key step to introduce the trihalomethyl moieties. When incubated with microsomes from yeast expressing human CYP21A2 or CYP17A1 with P450-oxidoreductase, CYP21A2 metabolized 17-fluoroprogesterone to a single product, whereas incubations with CYP17A1 gave no products. Halogenated steroids provide a robust system for exploring the substrate tolerance and catalytic plasticity of human steroid hydroxylases.


Assuntos
Microssomos/enzimologia , Pregnanos/síntese química , Esteroide 17-alfa-Hidroxilase/química , Esteroide 21-Hidroxilase/química , Esteroides Bromados/síntese química , Esteroides Clorados/síntese química , Esteroides Fluorados/síntese química , Colesterol Oxidase/química , Cromatografia Líquida de Alta Pressão , Ensaios Enzimáticos , Humanos , Microssomos/química , Oxirredução , Pregnanos/química , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Esteroide 17-alfa-Hidroxilase/metabolismo , Esteroide 21-Hidroxilase/metabolismo , Esteroides Bromados/química , Esteroides Clorados/química , Esteroides Fluorados/química , Especificidade por Substrato , Leveduras
3.
Clin Exp Dermatol ; 35(6): 614-7, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19874345

RESUMO

Anti-p200 pemphigoid and bullous pemphigoid (BP) are autoimmune subepidermal blistering diseases characterized by autoantibodies to a 200-kDa dermal antigen (p200) and two hemidesmosomal proteins (BP180 and BP230), respectively. We report a 70-year-old man with haemorrhagic blisters, widespread crusted erosions, and the immunopathological characteristics of anti-p200 pemphigoid. Treatment with doxycycline, topical corticosteroids and immunoadsorption led to rapid clinical remission. However, 19 weeks later, a relapse occurred with generalized itchy urticarial erythema and tense blisters. At this time, both strong dermal and epidermal IgG staining was detected by indirect immunofluorescence microscopy on salt-split skin, and autoantibodies against both p200 and the 16th noncollagenous (NC16A) domain of BP180 were found. Interestingly, the relapse was associated not only with the detection of autoantibodies to a second autoantigen (BP180), but also with an altered clinical phenotype. This case was a unique occasion to directly monitor the emergence of intermolecular epitope spreading during the course of an autoimmune bullous disorder.


Assuntos
Antibacterianos/uso terapêutico , Autoanticorpos/imunologia , Autoantígenos/imunologia , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/imunologia , Esteroides Clorados/uso terapêutico , Idoso , Clobetasol/uso terapêutico , Doxiciclina/uso terapêutico , Humanos , Masculino , Penfigoide Bolhoso/tratamento farmacológico , Penfigoide Bolhoso/patologia , Recidiva , Fatores de Tempo , Resultado do Tratamento
4.
Chem Biol ; 12(7): 779-87, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16039525

RESUMO

The goal of our work was the design of DNA-damaging agents that disrupt both DNA repair and signaling pathways in prostate tumor cells. A DNA alkylator (N,N-bis-2-chloroethyl aniline) was linked to a steroid ligand (17beta-hyroxy-estra-Delta(4(5),9(10))-3-one) to produce a complex molecule (11beta-dichloro) that forms DNA adducts that bind the androgen receptor (AR). We speculated that DNA adducts in an AR-DNA adduct complex would be camouflaged from DNA repair proteins that would otherwise remove the adducts in prostate cancer cells. Furthermore, transcription dependent on the AR would be antagonized by AR redistribution to sites distant from AR-driven promoters. The anticancer potential of 11beta-dichloro was demonstrated against prostate cancer cells in vitro and in vivo. 11beta-dichloro induces a unique pattern of gene disruption, induces apoptosis in apoptosis-resistant cells, and shows promising anticancer activity in animals.


Assuntos
Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Substâncias Intercalantes/farmacologia , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos , Androgênios , Animais , Adutos de DNA/química , Adutos de DNA/metabolismo , Estradiol/farmacologia , Ligantes , Masculino , Neoplasias da Próstata/genética , Esteroides Clorados/farmacologia , Células Tumorais Cultivadas
5.
Steroids ; 70(9): 563-72, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15923016

RESUMO

Osaterone acetate (17 alpha-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione; OA) is a steroidal antiandrogen. In order to clarify the species differences, metabolites of OA were examined in plasma, urine, and feces of dogs and humans after oral administration of OA. Eleven metabolites in plasma, urine, and feces were identified by their spectral properties and comparison to appropriate standards. The primary routes of OA metabolism involve 11 beta-, 15 beta- and 21-hydroxylation, 17 alpha-deacetylation, and dechlorination. Other metabolites arise from combinations of these pathways to form multiple oxidized metabolites. All metabolites observed in humans occurred in dogs. 11 beta-Hydroxylated metabolites (11 beta-OH OA and 11-oxo OA) were found in the plasma and urine of dogs, but there was no evidence of their presence in humans. 11 beta-Hydroxylation of exogenous steroids represents a distinctive biotransformation pathway.


Assuntos
Acetato de Clormadinona/análogos & derivados , Acetilação , Administração Oral , Antagonistas de Androgênios/sangue , Antagonistas de Androgênios/farmacocinética , Antagonistas de Androgênios/urina , Animais , Acetato de Clormadinona/química , Acetato de Clormadinona/metabolismo , Acetato de Clormadinona/farmacocinética , Cães , Fezes/química , Humanos , Hidroxilação , Estrutura Molecular , Especificidade da Espécie , Esteroides Clorados/metabolismo , Esteroides Clorados/farmacocinética
6.
Chemosphere ; 55(6): 839-47, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15041288

RESUMO

Six products were formed by reaction of ethynylestradiol (EE2) with sodium hypochlorite in buffered solutions. 4-Chloroethynylestradiol (4-ClEE2) and 2,4-dichloroethynylestradiol (2,4-diClEE2) were identified as the two major reaction products, using preparative HPLC, MS, and NMR. When EE2 reacted with chlorine at different pHs (pH 5, 7, and 9) or chlorine concentrations (0.2, 1, 2, and 5 mmol/l, corresponding to molar ratios to EE2, 1, 5, 10, and 25, respectively), the formation of 4-ClEE2 and 2,4-diClEE2 was observed under the above conditions, and the highest yields were 20 and 52 mol%, respectively. EE2 was consumed almost completely within 5 min of chlorination by addition of chlorine of more than 1 mmol/l (molar ratio to EE2, 5). On the other hand, the two products existed in highly chlorinated solutions after 60 min (4ClEE2, 1-6 mol%; 2,4-diClEE2, 3-25 mol%). The estrogenic activities of 4-ClEE2 by estrogen receptor alpha or beta binding assay were similar to those of the parent EE2, and the activities of 2,4-diClEE2 were lower about 10 times.


Assuntos
Etinilestradiol/química , Hipoclorito de Sódio/química , Esteroides Clorados/química , Cromatografia Líquida de Alta Pressão , Ensaio de Imunoadsorção Enzimática , Concentração de Íons de Hidrogênio , Cinética , Espectrometria de Massas
7.
Steroids ; 59(3): 176-80, 1994 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8048148

RESUMO

An efficient approach to 17-chloro-16(17) unsaturated D-homo antiprogestins is described. The key steps of the synthesis are a ring-expansion via dichlorocarbene addition to a 17-silyl enol ether and a palladium catalyzed coupling of an 11 beta-(4-aryltriflate) with tributyl(1-ethoxyethenyl)stannane or diethyl(3-pyridinyl)-borane. The new progesterone antagonists were tested for their biological activities and compared to those of known antiprogestins.


Assuntos
Progestinas/antagonistas & inibidores , Esteroides Clorados/síntese química , Esteroides Clorados/farmacologia , Aborto Induzido/métodos , Animais , Feminino , Estrutura Molecular , Gravidez , Ratos
8.
J Hand Surg Am ; 15(5): 748-50, 1990 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-2229972

RESUMO

A retrospective study of 235 patients with 338 primary trigger fingers determined the efficacy and safety of steroid injection. Initial treatment consisted of one to three injections of corticosteroid mixed with local anesthetic. Those fingers that failed injection therapy had conventional release of the first annular pulley. Seventy-seven percent of all fingers showed resolution or improvement; 49% after a single injection, 23% after two injections, and 5% after three injections.


Assuntos
Esteroides Clorados/uso terapêutico , Tenossinovite/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Injeções Intradérmicas , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Esteroides Clorados/administração & dosagem
9.
Food Chem Toxicol ; 27(4): 259-63, 1989 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-2731822

RESUMO

A method for the analysis of 3 beta-chloro steroids by high-performance liquid chromatography is described. These compounds are known to occur in commercial protein hydrolysates. The gastro-intestinal absorption, distribution and metabolism of chlorinated steroids were studied after their intragastric application to mice. At 2 hr after stomach intubation of 3 beta-chloro[4-14C]cholest-5-ene and 3 beta-chloro-[4-14C]stigmast-5-ene, large proportions of radioactivity had passed through the small intestine and were found to be concentrated in the contents of the caecum and colon. Very small amounts of 3 beta-chlorocholest-5-ene were absorbed by the intestinal mucosa and distributed to organs and tissues outside the alimentary canal, whereas intestinal permeability of 3 beta-chlorostigmast-5-ene was negligible. After administration of labelled 3 beta-chlorocholest-5-ene, the highest value of radioactivity, 120 Bq/g tissue, outside the intestinal tract was detected in liver. Altogether, less than 0.5% of the total radioactivity applied to the animals was found to be transported through the intestinal wall and less than 0.5% of the total radioactivity was detected in various metabolites. In general, 3 beta-chlorostigmast-5-ene was transported in smaller proportions and metabolized to a lesser extent than the corresponding cholesterol derivative. Moreover, metabolites of the two radioactive substrates formed by enzymatic attack of enteric micro-organisms were not detected in the contents of the caecum and colon. It appears that 3 beta-chlorinated steroids are fairly stable products that are metabolized poorly both by the cells of the intestinal mucosa and by enteric micro-organisms of mice.


Assuntos
Colestenos/farmacocinética , Sitosteroides , Esteroides Clorados/farmacocinética , Animais , Colestenos/administração & dosagem , Colestenos/análise , Cromatografia Líquida de Alta Pressão/métodos , Fezes/análise , Feminino , Absorção Intestinal , Intubação Gastrointestinal , Lipídeos/análise , Camundongos , Soja/análise , Distribuição Tecidual
10.
Drug Metab Dispos ; 17(1): 26-31, 1989.
Artigo em Inglês | MEDLINE | ID: mdl-2566465

RESUMO

The inactivation by 21-chlorinated steroids of rat liver cytochromes P-450 involved in the hydroxylation of progesterone and androstenedione has been investigated. Preincubation of intact liver microsomes from phenobarbital-treated rats with 21-chloropregnenolone, 21,21-dichloropregnenolone, or 21,21-dichloroprogesterone in the presence of NADPH caused a time-dependent decrease in progesterone 21-hydroxylase and in progesterone or androstenedione 6 beta-hydroxylase activity but had negligible or only minor effects on five other steroid hydroxylases. The compounds differed, however, with regard to the relative rate constants for inactivation of the 21- and 6 beta-hydroxylases. For example, 21,21-dichloroprogesterone and 21,21-dichloropregnenolone inactivated the progesterone 6 beta-hydroxylase at similar rates, but the dichloroprogesterone was a more effective inactivator of the 21-hydroxylase. The results indicate that the introduction of a dichloromethyl group into a substrate bearing a methyl group normally hydroxylated by only one or a few isozymes of cytochrome P-450 may be a rational means of designing isozyme-selective inhibitors but that target and nontarget enzymes may not totally retain the regioselectivity they exhibit towards the underivatized substrate.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Esteroides Clorados/farmacologia , Animais , Ativação Enzimática/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos , Esteroide Hidroxilases/metabolismo
11.
Steroids ; 45(5): 403-10, 1985 May.
Artigo em Inglês | MEDLINE | ID: mdl-3834659

RESUMO

Epimerizations of 16 alpha-chloro- (1a), bromo- (1b), and iodo-3 beta-hydroxy-5-androsten-17-one (1c) by a brief treatment with 0.2 equiv NaOH in aqueous pyridine reached equilibrium between 16 alpha- and 16 beta-halo ketones. 16 alpha-/16 beta-Halo ketone ratios at equilibrium were 1.5 for Cl, 1.25 for Br, and 1.0 for I. Kinetic analysis showed that compounds 1a-c were stereoselectively converted to the corresponding 16 alpha-hydroxy derivative 3 by an SN2 mechanism, in which the order of the apparent reactivity was Br greater than I greater than Cl. The hydrolysis of a number of 16 alpha-bromo-17-ketones and 2 alpha-bromo-3-ketones was carried out. The yields of the corresponding alcohols were found to depend on remote structural features in the steroids.


Assuntos
17-Cetosteroides , Esteroides Bromados , Esteroides Clorados , Fenômenos Químicos , Química , Hidrólise , Hidróxido de Sódio , Estereoisomerismo
12.
J Pharm Sci ; 70(10): 1154-7, 1981 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-6457907

RESUMO

Dehydroepiandrosterone sulfatide was prepared in a 68% yield by the reaction of 5-androstene-3 beta-ol-17-one 3 sulfate (silver salt) with dipalmitoyl alpha-iodopropylene glycol. The sulfatide was found to be a more potent inhibitor of human glucose-6-phosphate dehydrogenase than dehydroepiandrosterone. 16 alpha-Halogenated steroids also were prepared by direct halogenation of the steroid or indirect halogenation of an appropriate steroidal intermediate. Among various halogenated steroids, 16 alpha-bromoepiandrosterone was 50 times as potent as dehydroepiandrosterone as an inhibitor of glucose-6-phosphate dehydrogenase.


Assuntos
Desidroepiandrosterona/análogos & derivados , Esteroides Bromados/síntese química , Sulfoglicoesfingolipídeos/síntese química , Animais , Desidroepiandrosterona/síntese química , Eritrócitos/enzimologia , Glucosefosfato Desidrogenase/antagonistas & inibidores , Humanos , Camundongos , Esteroides Clorados/síntese química , Esteroides Fluorados/síntese química
14.
Chem Phys Lipids ; 24(2): 167-82, 1979 May.
Artigo em Inglês | MEDLINE | ID: mdl-455568

RESUMO

Treatment of 3 beta-benzoyloxy-14 alpha,15 alpha-epoxy-5 alpha-cholest-7-ene (I) with gaseous HCl in chloroform at -40 degrees C gave, in 87% yield, 3 beta-benzoyloxy-7 alpha,15 beta-dichloro-5 alpha cholest-8(14)-ene (III). Reduction of the latter compound with lithium aluminum hydride in ether at room temperature for 20 min gave, in 86% yield, 7 alpha-15 beta-dichloro-5 alpha-cholest-8(14)-en-3 beta-ol (IV). The latter compound was fully characterized and assignments of the individual carbon peaks in the 13C nuclear magnetic resonance spectra of this sterol have been completed. Reduction of III with excess lithium aluminum hydride in refluxing ether for 4 days gave, in 74% yield, 5 alpha-cholesta-7,14-dien-3 beta-ol (VI). Reduction of the dichloro-steryl benzoate III with lithium triethylborohydride in tetrahydrofuran gave, in 88% yield, 5 alpha-cholest-8(14)-en-3 beta-ol (VII). A similar reduction using lithium triethylborodeuteride led to the formation of [7 beta, 15 xi-2 H2]-VIIa. Treatment of III with concentrated HCl in a mixture of chloroform and methanol gave, in 79% yield, 3 beta-benzoyloxy-5 alpha-cholest-8(14)-en-15-one (II) which was characterized as such and as the corresponding free sterol.


Assuntos
Esteroides Clorados/síntese química , Células L/efeitos dos fármacos , Células L/metabolismo , Esteroides Clorados/farmacologia , Esteróis/biossíntese
16.
J Natl Cancer Inst ; 60(6): 1351-64, 1978 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-650701

RESUMO

Of 172 beagle dogs administered oral contraceptive steroids for 5-7 years, 114 developed 1,156 nodules in the mammary gland region. Most of these nodules arose 2.5-3.5 years after initiation of treatment. Approximately 16% of the nodules were transient and disappeared spontaneously from the mammary gland during the study. A total of 925 nodules were present in 99 dogs at the time of death or necropsy. These nodules were classified as benign mammary dysplasias (7.0%), lobular or intraductal hyperplasias (31.4%), simple adenomas (20.8%), complex adenomas (25.4%), benign mixed tumors (5.3%), malignant tumors (3.6%), or nonmammary lesions (6.5%). Histologically, the mammary nodules were representative primarily of the hyperplasias and tumors that occur spontaneously in the mammary glands of the dog. The only major exception was the presence of 82 simple adenomas that had basaloid features. Most of the contraceptive-related mammary nodules developed in dogs receiving the combination of progestion and mestranol at 10 or 25 times the proposed human dosage. Control dogs and dogs receiving mestrenol alone had few mammary nodules. Combinations of anagestone acetate and mestranol and chloroethynyl norgestrel (WY-4355) and mestranol produced large numbers of nodules at 10 and 25 times the proposed human dosage, whereas ethynerone plus mestranol produced large numbers of nodules only at 25 times the proposed human dosage. Ethynerone, when given alone at 25 times the proposed human dosage, was associated with fewer mammary nodules. Malignant neoplasms were seen in dogs given 10 and 25 times the proposed human dosage of anagestone acetate plus mestranol and 25 times the proposed human dosage of WY-4355 plus mestranol and ethynerone plus mestranol. This study strongly associates certain combinations of progestin and mestranol with mammary neoplasia in dogs.


Assuntos
Adenoma/induzido quimicamente , Anticoncepcionais Orais Sintéticos/toxicidade , Anticoncepcionais Orais/toxicidade , Neoplasias Mamárias Experimentais/induzido quimicamente , Adenoma/patologia , Animais , Anticoncepcionais Orais Combinados/toxicidade , Cães , Relação Dose-Resposta a Droga , Feminino , Neoplasias Mamárias Experimentais/patologia , Mestranol/toxicidade , Regressão Neoplásica Espontânea , Norgestrel/toxicidade , Norpregnadienos/toxicidade , Pregnenos/toxicidade , Congêneres da Progesterona/toxicidade , Esteroides Clorados/toxicidade , Fatores de Tempo
18.
J Med Chem ; 19(5): 721-3, 1976 May.
Artigo em Inglês | MEDLINE | ID: mdl-1271415

RESUMO

A number of number of 16alpha-alkoxy and 16alpha-acyloxy derivatives of 21-chloro-17-acyloxy corticosteroids have been prepared. The synthetic routes used were (a) reaction of the 16alpha,17-disubstituted 21-mesylate with lithium chloride and (b) reaction of the 16alpha-substituted 17,21-cyclic ortho ester with triphenylmethyl chloride. The vasoconstrictor activities in humans exhibited by these compounds were significantly lower than that of a 16beta-methyl analogue.


Assuntos
Pregnenodionas/síntese química , Vasoconstritores/síntese química , Valerato de Betametasona/farmacologia , Humanos , Pregnenodionas/farmacologia , Pele/efeitos dos fármacos , Esteroides Clorados/síntese química , Esteroides Clorados/farmacologia , Sistema Vasomotor/efeitos dos fármacos
20.
J Invest Dermatol ; 66(3): 157-60, 1976 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-129493

RESUMO

Formulations of a number of steroids were evaluated after topical application in a reversed passive Arthus test (RPA) in rabbits. Four 21-chlorosteroids in the same cream base were investigated. The preparations of SQ 18,566 (halcinonide) and SQ 20,811 showed anti-edema activity, but those of SQ 15,361 and SQ 20,589 were less active. Ointment formulations of halcinonide also reduced edema in the RPA. These results, coupled with previously reported clinical data, suggest that the RPA might be utilized to distinguish good from poor formulations of anti-inflammatory steroids prior to screening tests or clinical trials in humans.


Assuntos
Anti-Inflamatórios/uso terapêutico , Reação de Arthus/tratamento farmacológico , Inflamação/tratamento farmacológico , Administração Tópica , Animais , Glucocorticoides , Halcinonida/análogos & derivados , Injeções Intradérmicas , Pomadas , Pregnadienotrióis/administração & dosagem , Pregnadienotrióis/uso terapêutico , Pregnenodionas/administração & dosagem , Pregnenodionas/uso terapêutico , Coelhos , Esteroides Clorados/administração & dosagem , Esteroides Clorados/uso terapêutico , Triancinolona Acetonida/administração & dosagem , Triancinolona Acetonida/análogos & derivados , Triancinolona Acetonida/uso terapêutico
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