RESUMO
Nomifensine and three selected compounds from the series of H4a,H5-trans,H4a,H9b-cis-2,3,4,4a,5,9b-hexahydro-1H-in deno[1,2-b]pyridines have been resolved into their enantiomers. All compounds exhibit pronounced enantioselective activity with respect to their inhibition of tetrabenazine-induced ptosis and potentiation of yohimbine toxicity. Nomifensine exhibits the same preference for one enantiomer with respect to dopamine and norepinephrine reuptake, whereas in the indeno[1,2-b]pyridine series in vitro experiments do not discriminate between the optical antipodes. The absolute stereochemistry of the pharmacologically active enantiomers in both series was determined by X-ray analyses and comparative CD spectra. For biological activity the diphenylmethane is an essential structure feature in both series. Its absolute configuration proved to be 4S for nomifensine and 5S for indenopyridines. The similar pharmacological profile of the two chemical entities is therefore reflected in an identical configuration of this pharmacologically important molecular part.
Assuntos
Indanos/farmacologia , Indenos/farmacologia , Nomifensina/farmacologia , Piperidinas/farmacologia , Animais , Blefaroptose/induzido quimicamente , Blefaroptose/prevenção & controle , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fenômenos Químicos , Química , Dopamina/metabolismo , Sinergismo Farmacológico , Indanos/síntese química , Isomerismo , Masculino , Camundongos , Conformação Molecular , Norepinefrina/metabolismo , Piperidinas/síntese química , Ratos , Serotonina/metabolismo , Relação Estrutura-Atividade , Sinaptossomos/metabolismo , Tetrabenazina , Ioimbina/toxicidadeRESUMO
Since the discovery of the I(Ks)-potassium channel as the slowly activating component of the delayed rectifier current (I(k)) in cardiac tissue, the search for blockers of this current has been intense. During the screening of K(ATP)-channel openers of the chromanol type we found that chromanol 293B was able to block I(Ks). Chromanol 293B is a sulfonamide analogue of the K(ATP)-channel openers but had no activity on this target. Experiments were initiated to improve the activity and properties based on this lead compound. As a screening model we used Xenopus oocytes injected with human minK (KCNE1). Variations of the aromatic substituent and the sulfonamide group were prepared, and their activity was evaluated. We found that the greatest influence on activity was found in the aromatic substituents. The most active compounds were alkoxy substituted. We chose HMR1556 ((3R, 4S)-(+)-N-[-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-ethanesulfonamide) 10a for development as an antiarrhythmic drug. The absolute configuration, resulting from an X-ray single-crystal structure analysis, was determined.
Assuntos
Cromanos/síntese química , Bloqueadores dos Canais de Potássio , Bloqueadores dos Canais de Potássio/síntese química , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Sulfonamidas/síntese química , Animais , Cromanos/química , Cromanos/farmacologia , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Oócitos/fisiologia , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Xenopus laevisRESUMO
The characterization of the structure of mumbaistatin (1), an effective inhibitor of the glucose-6-phosphatase system (EC 3.1.3.9), is reported. Isolation of mumbaistatin from cultures of Streptomyces sp. DSM 11641 was achieved by anion-exchange and reversed-phase chromatography. The acid-labile inhibitor was methylated for the structure determination. Single-crystal X-ray structure analysis of a triply methylated dehydration product, C31H24O11, revealed the structure of an aromatic dispirodiketal (2), a compound containing a previously undescribed ring system. Extensive 2D-NMR experiments with mumbaistatin and with the methylation products showed that mumbaistatin itself possesses the hydroxydiketodicarboxylic acid structure 1, C28H20O12, which, in the presence of acid or upon activation through methyl ester formation, undergoes self-condensation with loss of water to the dispirodiketal form (2). Mumbaistatin is an anthraquinone derivative, whose open-chain diketo form acts as a specific and powerful inhibitor of glucose-6-phosphate translocase: IC50=5 nM. The activity towards the same enzyme of the cyclized dispirodiketal derivatives is roughly one thousand times lower.
Assuntos
Antraquinonas/química , Inibidores Enzimáticos/química , Fosfotransferases/antagonistas & inibidores , Streptomyces/metabolismo , Antraquinonas/síntese química , Antraquinonas/isolamento & purificação , Antiporters , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Ciclização , Inibidores Enzimáticos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Metilação , Conformação Molecular , Proteínas de Transporte de Monossacarídeos , Espectrofotometria Ultravioleta , Streptomyces/químicaRESUMO
Two novel compounds, kodaistatin A, C35H34O11, molecular weight 630, and kodaistatin C, C35H34O12, molecular weight 646, have been isolated from cultures of Aspergillus terreus Thom DSM 11247 by solid-phase extraction, size-exclusion chromatography, and various preparative HPLC steps. The use of a range of 2D NMR measurements, in particular 13C-13C correlation measurements, has led to the clarification of the structure of kodaistatin A. Kodaistatin C is a hydroxylated derivative of kodaistatin A. Both natural products contain hydroxylated aspulvinones and identical highly substituted polyketide units. An X-ray single crystal structure analysis of aspulvinon E demonstrated the z-configuration at the central double bond. The kodaistatins are effective inhibitors of the glucose-6-phosphate translocase component of the glucose-6-phosphatase system (EC 3.1.3.9), an enzyme system which is important for the control of blood glucose levels. The IC50 is 80 nM for kodaistatin A and 130 nM for kodaistatin C.
Assuntos
Aspergillus/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fosfotransferases/antagonistas & inibidores , Animais , Antiporters , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/enzimologia , Inibidores Enzimáticos/isolamento & purificação , Concentração Inibidora 50 , Lactonas/química , Lactonas/isolamento & purificação , Lactonas/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Proteínas de Transporte de Monossacarídeos , RatosRESUMO
Aurantimycins A (1), B (2) and C (3) were isolated from the mycelium of Streptomyces aurantiacus JA 4570 as new representatives of the azinothricin group of hexadepsipeptide antibiotics. Their structures were settled by X-ray diffraction analysis of crystalline aurantimycin A (1), high field homo- and heteronuclear 2D NMR experiments, high-resolution mass spectrometry and amino acid analysis. Aurantimycins are characterized by a new side chain containing fourteen carbon atoms. They display strong activity against Gram-positive bacteria and cytotoxic effects against L-929 mouse fibroblast cells.
Assuntos
Antibacterianos/biossíntese , Peptídeos , Streptomyces/metabolismo , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Linhagem Celular , Citotoxinas/biossíntese , Citotoxinas/química , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Difração de Raios XAssuntos
Plaquetas/efeitos dos fármacos , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Difosfato de Adenosina/farmacologia , Animais , Cães , Humanos , Estrutura Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Crystal structures are reported for various co-crystals of rccc-resorcarenes with triethylammonium chloride. Usually, two molecules of a C2v-symmetric tetraester 2 in the boat conformation are linked through four hydrogen-bonded chloride anions to give dimeric assemblies. Two of the chloride anions may be replaced by four hydrogen-bonded ethanol molecules in an otherwise similar structure. These assemblies, which consist of six or eight components, posses voluminous, negatively charged chambers in which two triethylammionium cations, 3+, are included as guests by strong electrostatic and hydrogen-bonding interactions. The host-guest N-H...Cl hydrogen bonds were clearly detected at 173 K. These are the first examples of hydrogen-bonded, solid-state capsules trapping two ions of the same charge in close proximity. In the 1:2 complex with 3+ Cl-, the molecule of the parent resorcarene 1 also adopts a boat conformation whose cavity is considerably extended by four hydrogen-bonded chloride anions. The pocket formed in this way again includes two 3+ ions as a result of electrostatic and hydrogen bonding host-guest interactions. All these structures show that the boat conformers of resorcarenes can be used as a novel motif for the construction of hydrogen-bonded assemblies capable of molecular inclusion and encapsulation.