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1.
Fitoterapia ; 131: 221-224, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30414875

RESUMO

A novel cytotoxic 20-norsteroid with twenty-six carbon atoms named acemosin (1) was isolated and structural characterized together with two known compounds, asparacosin A (2) and stigmasterol (3) from the roots of Asparagus racemosus. Their structures were elucidated by a combination of 2D NMR, HR-MS and X-ray crystallographic analyses. Acemosin (1) possesses an unprecedented carbon skeleton, where the methyl group at C-20 is absent. Acemosin shows moderate cytotoxicity against HepG2 cancer cell line with its IC50 value of 87.3 µg/mL.


Assuntos
Asparagus (Planta)/química , Noresteroides/isolamento & purificação , Raízes de Plantas/química , Células Hep G2 , Humanos , Laos , Estrutura Molecular , Noresteroides/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
2.
J Org Chem ; 82(15): 7974-7979, 2017 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-28691489

RESUMO

Matsutakone (1), a novel sterol with an unprecedented polycyclic ring system, together with a new norsteroid matsutoic acid (2) were isolated from the fruiting bodies of Tricholoma matsutake. Their structures and absolute configurations were assigned by extensive spectroscopic analyses and computational methods. Bioassay results showed that compounds 1 and 2 exhibited inhibitory activities against acetylcholinesterase (IC50 20.9 µM for 1).


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Noresteroides/farmacologia , Esteróis/farmacologia , Tricholoma/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Relação Dose-Resposta a Droga , Eritrócitos/enzimologia , Humanos , Conformação Molecular , Noresteroides/química , Noresteroides/isolamento & purificação , Esteróis/química , Esteróis/isolamento & purificação , Relação Estrutura-Atividade
3.
Mar Drugs ; 15(6)2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28617320

RESUMO

Two new steroids, crellasterones A (1) and B (2), together with the previously reported compound chalinasterol (3) and several nucleosides (4-7), were isolated from the sponge Crella incrustans, collected in New Caledonia. The structures of the new compounds were established by extensive NMR and mass spectroscopic analysis and revealed unprecedented marine natural products with a ring-contracted A-norsterone nucleus and 2-hydroxycyclopentenone chromophore. The absolute configurations were derived from electronic circular dichroism (ECD) measurements in conjunction with high-level density functional theory (DFT) calculations.


Assuntos
Noresteroides/isolamento & purificação , Poríferos/química , Animais , Espectroscopia de Ressonância Magnética , Noresteroides/química
4.
J Steroid Biochem Mol Biol ; 165(Pt B): 268-276, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27452335

RESUMO

Liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. The ability of LXRs to integrate metabolic and inflammation signalling makes them attractive targets for intervention in human metabolic diseases. Several oxidized metabolites of cholesterol (oxysterols) are endogenous LXR ligands, that modulate their transcriptional responses. While 25R-cholestenoic acid is an agonist of the LXRs, the synthetic analogue 27-norcholestenoic acid that lacks the 25-methyl is an inverse agonist. This change in the activity profile is triggered by a disruption of a key interaction between residues His435 and Trp457 that destabilizes the H11-H12 region of the receptor and favors the binding of corepressors. The introduction of fluorine atoms on the oxysterol side chain can favor both hydrophobic interactions as well as hydrogen bonds with the fluorine atoms and may thus induce changes in the receptor that may lead to changes in the activity profile. To evaluate these effects we have synthesized two fluorinated 27-nor-steroids, analogues of 27-norcholestenoic acid, the 25,25-difluoroacid and the corresponding 26-alcohol. The key step was a Reformatsky reaction on the C-24 cholenaldehyde, with ethyl bromodifluoroacetate under high intensity ultrasound (HIU) irradiation, followed by a Barton-McCombie type deoxygenation. Activity was evaluated in a luciferase reporter assay in the human HEK293T cells co-transfected with full length human LXRß expression vector. The 25,25-difluoro-27-norcholestenoic acid was an inverse agonist and antagonist similar to its non-fluorinated analogue while its reduced derivative 25,25-difluoro-27-norcholest-5-ene-3ß,26-diol was an agonist. Molecular dynamics simulation of the ligand-receptor complexes showed that the difluoroacid disrupted the His435-Trp457 interaction although the resulting conformational changes were different from those induced by the non-fluorinated analogue. In the case of the difluoroalcohol, the fluorine atoms actively participated in the interaction with several residues in the ligand binding pocket leading to a stabilization of the active receptor conformation.


Assuntos
Colestenos/química , Flúor/química , Hidroxicolesteróis/química , Receptores X do Fígado/agonistas , Noresteroides/química , Oxisteróis/química , Álcoois/química , Benzoatos/química , Benzilaminas/química , Colesterol/química , Células HEK293 , Humanos , Ligação de Hidrogênio , Ligantes , Receptores X do Fígado/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Ligação Proteica , Transdução de Sinais , Distribuição Tecidual
5.
Bioorg Med Chem Lett ; 26(20): 4966-4969, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27623548

RESUMO

Columnaristerol A (1), a rare natural 19-norsterol possessing a 10ß-hydroxy group was isolated from the Formosan octocoral Nephthea columnaris, and its structure was elucidated by spectroscopic methods. Sterol 1 was found to be a cytotoxic agent that exhibited in vitro moderate cytotoxic activity against MOLT-4 and SUP-T1 human leukemia-lymphoma cell lines.


Assuntos
Antozoários/metabolismo , Noresteroides/química , Noresteroides/farmacologia , Esteróis/química , Esteróis/farmacologia , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade , Taiwan
6.
Arch Pharm Res ; 38(1): 18-25, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25231340

RESUMO

Three new sterols, 5α,8α-epidioxy-24-norcholesta-6,9(11),22-trien-3ß-ol (1), 5α,8α-epidioxy-cholesta-6,9(11),24-trien-3ß-ol (2), and 5α,8α-epidioxy-cholesta-6,23-dien-3ß,25-diol (3), with four known sterols (4-7) were isolated from a marine sponge Monanchora sp. Their chemical structures were elucidated by extensive spectroscopic analysis. Compounds 1 and 3-7 showed moderate cytotoxicity against several human carcinoma cell lines including renal (A-498), pancreatic (PANC-1 and MIA PaCa-2), and colorectal (HCT 116) cancer cell lines.


Assuntos
Colestadienóis/isolamento & purificação , Colestadienóis/farmacologia , Colestenos/isolamento & purificação , Colestenos/farmacologia , Noresteroides/isolamento & purificação , Noresteroides/farmacologia , Poríferos/química , Esteróis/isolamento & purificação , Esteróis/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Esteróis/toxicidade
7.
Br J Pharmacol ; 172(5): 1333-47, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25377730

RESUMO

BACKGROUND AND PURPOSE: Memantine and ketamine are clinically used, open-channel blockers of NMDA receptors exhibiting remarkable pharmacodynamic similarities despite strikingly different clinical profiles. Although NMDA channel gating constitutes an important difference between memantine and ketamine, it is unclear how positive allosteric modulators (PAMs) might affect the pharmacodynamics of these NMDA blockers. EXPERIMENTAL APPROACH: We used two different PAMs: SGE-201, an analogue of an endogenous oxysterol, 24S-hydroxycholesterol, along with pregnenolone sulphate (PS), to test on memantine and ketamine responses in single cells (oocytes and cultured neurons) and networks (hippocampal slices), using standard electrophysiological techniques. KEY RESULTS: SGE-201 and PS had no effect on steady-state block or voltage dependence of a channel blocker. However, both PAMs increased the actions of memantine and ketamine on phasic excitatory post-synaptic currents, but neither revealed underlying pharmacodynamic differences. SGE-201 accelerated the re-equilibration of blockers during voltage jumps. SGE-201 also unmasked differences among the blockers in neuronal networks - measured either by suppression of activity in multi-electrode arrays or by neuroprotection against a mild excitotoxic insult. Either potentiating NMDA receptors while maintaining the basal activity level or increasing activity/depolarization without potentiating NMDA receptor function is sufficient to expose pharmacodynamic blocker differences in suppressing network function and in neuroprotection. CONCLUSIONS AND IMPLICATIONS: Positive modulation revealed no pharmacodynamic differences between NMDA receptor blockers at a constant voltage, but did expose differences during spontaneous network activity. Endogenous modulator tone of NMDA receptors in different brain regions may underlie differences in the effects of NMDA receptor blockers on behaviour.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Hidroxicolesteróis/farmacologia , Noresteroides/farmacologia , Pregnenolona/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Hidroxicolesteróis/química , Noresteroides/química , Pregnenolona/química , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade
8.
Zhong Yao Cai ; 37(3): 432-5, 2014 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-25174108

RESUMO

OBJECTIVE: To study the chemical constituents in the seeds of Ziziphus mauritiana. METHODS: The constituents were isolated by silica column chromatography and their structures were elucidated by physico-chemical properties and spectroscopic analysis. RESULTS: Twelve compounds were isolated from the seeds of Ziziphus mauritiana and identified as betulinic aldehyde (1), betulinic acid (2), ceanothic acid (3), frangufoline (4), spinosin (5), beta-sitosterol (6), daucosterol (7), daucosterol-6'-octadecanoate (8), sucrose (9), docosanoic acid (10), stearic acid (11), palmitoleic acid (12). CONCLUSION: All the compounds are obtained from Ziziphus mauritiana seeds for the first time and compounds 4,5 and 8 are isolated from this plant for the first time.


Assuntos
Extratos Vegetais/química , Plantas Medicinais/química , Sementes/química , Ziziphus/química , Flavonoides/química , Flavonoides/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Noresteroides/química , Noresteroides/isolamento & purificação , Extratos Vegetais/isolamento & purificação
9.
J Bacteriol ; 196(20): 3598-608, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25092028

RESUMO

Comamonas testosteroni TA441 degrades steroids via aromatization and meta-cleavage of the A ring, followed by hydrolysis, and produces 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid as an intermediate compound. Herein, we identify a new intermediate compound, 9α-hydroxy-17-oxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid. Open reading frame 28 (ORF28)- and ORF30-encoded acyl coenzyme A (acyl-CoA) dehydrogenase was shown to convert the CoA ester of 9α-hydroxy-17-oxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid to the CoA ester of 9α-hydroxy-17-oxo-1,2,3,4,10,19-hexanorandrost-6-en-5-oic acid. A homology search of the deduced amino acid sequences suggested that the ORF30-encoded protein is a member of the acyl-CoA dehydrogenase_fadE6_17_26 family, whereas the deduced amino acid sequence of ORF28 showed no significant similarity to specific acyl-CoA dehydrogenase family proteins. Possible steroid degradation gene clusters similar to the cluster of TA441 appear in bacterial genome analysis data. In these clusters, ORFs similar to ORFs 28 and 30 are often found side by side and ordered in the same manner as ORFs 28 and 30.


Assuntos
Comamonas testosteroni/metabolismo , Noresteroides/metabolismo , Esteroides/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Estrutura Molecular , Mutação , Noresteroides/química , Fases de Leitura Aberta , Esteroides/química
10.
J Pharm Pharmacol ; 66(10): 1377-87, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24821499

RESUMO

OBJECTIVES: To assess the role of intestinal lymphatic transport in the oral bioavailability and brain deposition of a highly lipophilic, centrally acting drug candidate (Org 49209) in comparison to cholesterol, a close structural analogue. METHODS: The intestinal lymphatic transport of Org 49209 and cholesterol was assessed in lymph-cannulated anaesthetised rats and total bioavailability evaluated in non-lymph-cannulated animals. Parallel groups were employed to examine the brain deposition of Org 49209 after intraduodenal and intraperitoneal administrations. KEY FINDINGS: The contribution of intestinal lymphatic transport to total bioavailability was similar for Org 49209 and cholesterol (approximately 40% of the absorbed dose). However, the oral bioavailability of Org 49209 was significantly (fourfold) lower than cholesterol. Brain deposition of Org 49209 was similar after intraduodenal and intraperitoneal administration. Systemic exposure, however, was higher after intraduodenal administration and brain-to-plasma ratios were therefore reduced. CONCLUSION: The oral bioavailability of Org 49209 was significantly lower than that of its structural analogue cholesterol; however, intestinal lymphatic transport played a similar role in oral bioavailability for both compounds. Brain to plasma ratios were lower after intraduodenal versus intraperitoneal administration, suggesting that drug association with intestinal lymph lipoproteins may limit central nervous system access for highly lipophilic drugs.


Assuntos
Encéfalo/metabolismo , Fármacos do Sistema Nervoso Central/farmacocinética , Colesterol/análogos & derivados , Colesterol/farmacocinética , Mucosa Intestinal/metabolismo , Linfa/metabolismo , Sistema Linfático/metabolismo , Noresteroides/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Transporte Biológico , Fármacos do Sistema Nervoso Central/metabolismo , Colesterol/metabolismo , Absorção Intestinal , Lipoproteínas/metabolismo , Masculino , Estrutura Molecular , N-Metilaspartato/metabolismo , Noresteroides/metabolismo , Ratos Sprague-Dawley , Esquizofrenia/metabolismo
11.
Proc Natl Acad Sci U S A ; 111(22): 7931-5, 2014 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-24843125

RESUMO

Highly concise and stereospecific routes to cis and trans fusion, carrying various functionality at one of the bridgehead carbons, have been accomplished.


Assuntos
Reação de Cicloadição/métodos , Ciclobutanos/química , Estrogênios/síntese química , Noresteroides/síntese química , Estereoisomerismo , Alquilação , Indústria Farmacêutica/métodos , Metilação , Modelos Moleculares
12.
J Neurosci ; 33(44): 17290-300, 2013 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-24174662

RESUMO

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are critical to the regulation of excitatory synaptic function in the CNS. NMDARs govern experience-dependent synaptic plasticity and have been implicated in the pathophysiology of various neuropsychiatric disorders including the cognitive deficits of schizophrenia and certain forms of autism. Certain neurosteroids modulate NMDARs experimentally but their low potency, poor selectivity, and very low brain concentrations make them poor candidates as endogenous ligands or therapeutic agents. Here we show that the major brain-derived cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC) is a very potent, direct, and selective positive allosteric modulator of NMDARs with a mechanism that does not overlap that of other allosteric modulators. At submicromolar concentrations 24(S)-HC potentiates NMDAR-mediated EPSCs in rat hippocampal neurons but fails to affect AMPAR or GABAA receptors (GABA(A)Rs)-mediated responses. Cholesterol itself and other naturally occurring oxysterols present in brain do not modulate NMDARs at concentrations ≤10 µM. In hippocampal slices, 24(S)-HC enhances the ability of subthreshold stimuli to induce long-term potentiation (LTP). 24(S)-HC also reverses hippocampal LTP deficits induced by the NMDAR channel blocker ketamine. Finally, we show that synthetic drug-like derivatives of 24(S)-HC, which potently enhance NMDAR-mediated EPSCs and LTP, restore behavioral and cognitive deficits in rodents treated with NMDAR channel blockers. Thus, 24(S)-HC may function as an endogenous modulator of NMDARs acting at a novel oxysterol modulatory site that also represents a target for therapeutic drug development.


Assuntos
Colesterol/metabolismo , Hipocampo/metabolismo , Hidroxicolesteróis/metabolismo , Hidroxicolesteróis/farmacologia , Receptores de N-Metil-D-Aspartato/fisiologia , Potenciais de Ação/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Feminino , Masculino , Camundongos , Noresteroides/metabolismo , Noresteroides/farmacologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley
13.
Steroids ; 78(2): 234-40, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23178256

RESUMO

Treatment of 12-oxosteroids with PhI(OAc)(2) and KOH in refluxing methanol triggers a quasi-Favorskii C-ring contraction leading to the corresponding 11α-alcoxycarbonyl-C-norsteroids in moderate yields. This constitutes the first one-step synthetic alternative to C-norsteroids starting from 12-oxosteroids.


Assuntos
Iodo/química , Cetosteroides/química , Noresteroides/química , Cristalografia por Raios X , Hidrólise , Cetosteroides/síntese química , Conformação Molecular , Noresteroides/síntese química
14.
Molecules ; 17(7): 7769-81, 2012 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-22732888

RESUMO

Two viridin-related B-norsteroids, B-norviridiol lactone (1) and B-norviridin enol (2), both possessing distinct unprecedented carbon skeletons, were isolated from a liquid culture of the ash dieback-causing fungus Hymenoscyphus pseudoalbidus. Compound 2 was found to degrade to a third B-norsteroidal compound, 1ß-hydroxy-2α-hydro-asterogynin A (3), which was later detected in the original culture. The proposed structure of 1 is, regarding connectivity, identical to the original erroneous structure for TAEMC161, which was later reassigned as viridiol. Compound 2 showed an unprecedented ¹H-¹³C HMBC correlation through an intramolecular hydrogen bond. The five-membered B-ring of compounds 1-3 was proposed to be formed by a benzilic acid rearrangement. The known compound asterogynin A was found to be formed from 3 by a ß-elimination of water. All compounds were characterized by NMR spectroscopy, LC-HRMS and polarimetry.


Assuntos
Ascomicetos/química , Noresteroides/isolamento & purificação , Androstenodióis/química , Espectroscopia de Ressonância Magnética , Noresteroides/química , Esteróis/química
15.
J Lipid Res ; 52(1): 87-97, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20921334

RESUMO

3ß-Hydroxy-5-oxo-5,6-secocholestan-6-al (secosterol-A) and its aldolization product 3ß-hydroxy-5ß-hydroxy-B-norcholestane-6ß-carboxaldehyde (secosterol-B) were recently detected in human atherosclerotic tissues and brain specimens, and they may play pivotal roles in the pathogenesis of atherosclerosis and neurodegenerative diseases. However, as their origin remains unidentified, we examined the formation mechanism, the stability, and the fate of secosterols in vitro and in vivo. About 40% of secosterol-A remained unchanged after 3 h incubation in the FBS-free medium, whereas 20% and 40% were converted to its aldehyde-oxidation product, 3ß-hydroxy-5-oxo-secocholestan-6-oic acid, and secosterol-B, respectively. In the presence of FBS, almost all secosterol-A was converted immediately to these compounds. Secosterol-B in the medium, with and without FBS, was relatively stable, but ∼30% was converted to its aldehyde-oxidation product, 3ß-hydroxy-5ß-hydroxy-B-norcholestane-6-oic acid (secoB-COOH). When neutrophil-like differentiated human leukemia HL-60 (nHL-60) cells activated with PMA were cultured in the FBS-free medium containing cholesterol, significantly increased levels of secosterol-A and its aldehyde-oxidation product, but not secosterol-B, were formed. This secosterol-A formation was decreased in the culture of PMA-activated nHL-60 cells containing several reactive oxygen species (ROS) inhibitors and scavengers or in the culture of PMA-activated neutrophils isolated from myeloperoxidase (MPO)-deficient mice. Our results demonstrate that secoterol-A is formed by an ozone-like oxidant generated with PMA-activated neutrophils through the MPO-dependent mechanism.


Assuntos
Colestanol/análogos & derivados , Colestanonas/metabolismo , Colesterol/metabolismo , Noresteroides/metabolismo , Ozônio/metabolismo , Peroxidase/metabolismo , Secoesteroides/metabolismo , Animais , Diferenciação Celular , Colestanol/metabolismo , Células HL-60 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
16.
Nat Prod Commun ; 5(10): 1571-4, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21121250

RESUMO

Two ring-A-aromatized bile acids, 1 and 2, were isolated from the sponge Sollasella moretonensis, collected from the seabed of northern Queensland. Structures were assigned on the basis of extensive 1D and 2D NMR studies, as well as analysis by HRESIMS. Compound 2 has previously been produced synthetically, though this marks its first isolation from a natural source.


Assuntos
Ácidos e Sais Biliares/isolamento & purificação , Colenos/isolamento & purificação , Poríferos/química , Animais , Ácidos e Sais Biliares/química , Noresteroides/isolamento & purificação
17.
J Nat Prod ; 73(11): 1780-4, 2010 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-21043476

RESUMO

7-Nor-ergosterolide (1), a rare 7-norsteroid with an unusual pentalactone B-ring system, and two new steroid derivatives, 3ß,11α-dihydroxyergosta-8,24(28)-dien-7-one (2) and 3ß-hydroxyergosta-8,24(28)-dien-7-one (3), were characterized from the culture extract of Aspergillus ochraceus EN-31, an endophytic fungus isolated from the marine brown alga Sargassum kjellmanianum. In addition, nine known related steroids were isolated and identified. The structures of these compounds were established on the basis of extensive spectroscopic analysis. The absolute configuration of the new steroids (1-3) was determined by application of the modified Mosher's method. Compound 1, which represents the first example of a 7-nor-ergosteroid possessing a pentalactone B-ring system in a naturally occurring steroid, displayed cytotoxicity against NCI-H460, SMMC-7721, and SW1990 cell lines with IC(50) values of 5.0, 7.0, and 28.0 µg/mL, respectively. Compound 2 also displayed cytotoxicity against the SMMC-7721 cell line with an IC(50) value of 28.0 µg/mL.


Assuntos
Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Aspergillus ochraceus/química , Noresteroides/química , Noresteroides/isolamento & purificação , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Biologia Marinha , Estrutura Molecular , Noresteroides/farmacologia , Ressonância Magnética Nuclear Biomolecular , Feófitas/microbiologia , Estereoisomerismo
18.
Acta Crystallogr C ; 66(Pt 4): o185-6, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20354306

RESUMO

The title compound, C(19)H(26)O(2), a B-norandrogen with a 6beta-methyl group, is a recently identified and experimentally tested potent new aromatase inhibitor. It shares structural and physicochemical similarities both with the natural substrate of the enzyme, androstenedione, and with exemestane, another potent aromatase inhibitor having a 6-methylidene group. X-ray diffraction results indicate that the B-nor molecule and exemestane have nearly the same oxygen-oxygen and methyl-methyl separations, though they have distinct configurations of the hydrophobic groups at the 6-position. These structural comparisons allow correlations to be inferred between the active site geometry of the molecules and the aromatase inhibition power of the studied compound.


Assuntos
Androstadienos/química , Androstenodiona/química , Inibidores da Aromatase/química , Noresteroides/química , Androstenodiona/farmacologia , Inibidores da Aromatase/farmacologia , Sítios de Ligação , Catálise , Cristalografia por Raios X , Estrutura Molecular , Ligação Proteica , Difração de Raios X
19.
Biol Chem ; 391(1): 119-27, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19919183

RESUMO

Anabolic-androgenic steroids are some of the most frequently misused drugs in human sports. Recently, a previously unknown urinary metabolite of metandienone, 17beta-hydroxymethyl-17 alpha-methyl-18-norandrosta-1,4,13-trien-3-one (20OH-NorMD), was discovered via LC-MS/MS and GC-MS. This metabolite was reported to be detected in urine samples up to 19 days after administration of metandienone. However, so far it was not possible to obtain purified reference material of this metabolite and to confirm its structure via NMR. Eleven recombinant strains of the fission yeast Schizosaccharomyces pombe that express different human hepatic or steroidogenic cytochrome P450 enzymes were screened for production of this metabolite in a whole-cell biotransformation reaction. 17,17-Dimethyl-18-norandrosta-1,4,13-trien-3-one, chemically derived from metandienone, was used as substrate for the bioconversion, because it could be converted to the final product in a single hydroxylation step. The obtained results demonstrate that CYP21 and to a lesser extent also CYP3A4 expressing strains can catalyze this steroid hydroxylation. Subsequent 5 l-scale fermentation resulted in the production and purification of 10 mg of metabolite and its unequivocal structure determination via NMR. The synthesis of this urinary metandienone metabolite via S. pombe-based whole-cell biotransformation now allows its use as a reference substance in doping control assays.


Assuntos
Anabolizantes/urina , Metandrostenolona/análogos & derivados , Metandrostenolona/urina , Noresteroides/metabolismo , Biotransformação , Citocromo P-450 CYP3A/metabolismo , Doping nos Esportes/prevenção & controle , Humanos , Espectrometria de Massas , Metandrostenolona/metabolismo , Noresteroides/urina , Ressonância Magnética Nuclear Biomolecular , Proteínas Recombinantes/metabolismo , Schizosaccharomyces/enzimologia , Esteroide 21-Hidroxilase/metabolismo , Detecção do Abuso de Substâncias/métodos
20.
J Biol Chem ; 285(2): 1113-21, 2010 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-19889628

RESUMO

Norursodeoxycholic acid (norUDCA) exhibits efficient anti-cholestatic properties in an animal model of sclerosing cholangitis. norUDCA is eliminated as a C(23)-ester glucuronide (norUDCA-23G) in humans. The present study aimed at identifying the human UDP-glucuronosyltransferase (UGT) enzyme(s) involved in hepatic norUDCA glucuronidation and at evaluating the consequences of single nucleotide polymorphisms in the coding region of UGT genes on norUDCA-23G formation. The effects of norUDCA on the formation of the cholestatic lithocholic acid-glucuronide derivative and of rifampicin on hepatic norUDCA glucuronidation were also explored. In vitro glucuronidation assays were performed with microsomes from human tissues (liver and intestine) and HEK293 cells expressing human UGT enzymes and variant allozymes. UGT1A3 was identified as the major hepatic UGT enzyme catalyzing the formation of norUDCA-23G. Correlation studies using samples from a human liver bank (n = 16) indicated that the level of UGT1A3 protein is a strong determinant of in vitro norUDCA glucuronidation. Analyses of the norUDCA-conjugating activity by 11 UGT1A3 variant allozymes identified three phenotypes with high, low, and intermediate capacity. norUDCA is also identified as a competitive inhibitor for the hepatic formation of the pro-cholestatic lithocholic acid-glucuronide derivative, whereas norUDCA glucuronidation is weakly stimulated by rifampicin. This study identifies human UGT1A3 as the major enzyme for the hepatic norUDCA glucuronidation and supports that some coding polymorphisms affecting the conjugating activity of UGT1A3 in vitro may alter the pharmacokinetic properties of norUDCA in cholestasis treatment.


Assuntos
Ácidos Cólicos/química , Glucuronídeos/química , Glucuronosiltransferase/química , Microssomos Hepáticos/enzimologia , Noresteroides/química , Animais , Linhagem Celular , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/enzimologia , Colangite Esclerosante/genética , Ácidos Cólicos/uso terapêutico , Modelos Animais de Doenças , Ésteres/química , Ésteres/metabolismo , Glucuronídeos/biossíntese , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Noresteroides/uso terapêutico , Polimorfismo Genético , Rifampina/química
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