RESUMEN
MDL 62,879 (GE2270A) 1 is a new inhibitor of elongation factor-Tu (EF-Tu) and belongs to the class of thiazolyl peptide antibiotics. Controlled acid hydrolysis of 1 followed by treatment with base resulted in the lost of the two terminal amino acids and in the formation of water-soluble MDL 62,935 2. Although less active in vitro than its parent compound, 2 was able to inhibit by 50% an Escherichia coli cell-free protein synthesis system at roughly the same concentration of 1. MDL 62,935 2 was subjected to further modification at the beta-phenylserine residue. Derivatives obtained from 2 were less active in both antimicrobial (MIC) and enzymatic (IC50) assays. This suggests that beta-phenylserine plays an important role for the inhibition of EF-Tu by 1 and 2.
Asunto(s)
Antibacterianos/farmacología , Factor Tu de Elongación Peptídica/antagonistas & inhibidores , Acetilación , Antibacterianos/síntesis química , Antibacterianos/química , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacologíaAsunto(s)
Acetilglucosamina/análogos & derivados , Antifúngicos/farmacología , Quitina/metabolismo , Compuestos de Dansilo/metabolismo , Colorantes Fluorescentes/metabolismo , Acetilglucosamina/síntesis química , Acetilglucosamina/metabolismo , Candida albicans/efectos de los fármacos , Candida albicans/metabolismo , Pared Celular/efectos de los fármacos , Quitina Sintasa/antagonistas & inhibidores , Compuestos de Dansilo/síntesis química , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Colorantes Fluorescentes/química , Nucleósidos de Pirimidina/farmacologíaRESUMEN
New N-acyl derivatives of 1-N-desmethyl goldinamine were obtained from degradation of kirromycin. Periodate-oxidation of these derivatives provided new aldehydic fragments that were further elaborated. Both N-phenyl ureido and N-phthalimido derivatives of 1-N-desmethyl goldinamine are able to inhibit bacterial protein synthesis in cell-free assay and are active against whole microorganisms, although with lower potency than kirromycin. The derivatives from the aldehydic fragments are totally inactive.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Proteínas Bacterianas/biosíntesis , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxidación-Reducción , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Ftalimidas/síntesis química , Ftalimidas/química , Ftalimidas/farmacología , Piridonas/síntesis química , Piridonas/química , Piridonas/farmacología , Relación Estructura-ActividadAsunto(s)
Antibacterianos/química , Tiazoles/química , Actinomycetales/metabolismo , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Cromatografía Líquida de Alta Presión , Fermentación , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptidos Cíclicos , Espectrometría de Masa Bombardeada por Átomos Veloces , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
GE2270 A, produced by Planobispora rosea ATCC 53773, inhibits Gram-positive bacteria and anaerobes by acting on the bacterial protein synthesis. The structure has been determined by physico-chemical methods applied to the intact molecule and to the main hydrolysis products. Characterization by UV, IR, NMR (double quantum filter COSY), acid-base ionization, elemental analysis and FAB-MS indicated that GE2270 A is a highly modified peptide having MW 1,289 and formula C56H55N15O10S6, and a weak basic function, and that it belongs to the thiazolyl peptide group of antibiotics. Acid hydrolysis yielded a main product (MW 634), responsible for the chromophoric absorption, and a number of hydrolyzed products of lower MW. 13C NMR inverse techniques and MS studies (EI, positive ion chemical ionization, and collision induced dissociation FAB-MS-MS experiments) on GE2270 A, the chromophoric compound, and the other hydrolysis products led to the complete identification of the various amino acid residues and their sequence. Two out of the six chiral centers have been determined. The structure is thought to originate from modification of a chain of 14 amino acids in a process which creates 6 thiazole rings and one pyridine. The modification process also closes the linear polypeptide to form a cyclic part with an attached side-chain. GE2270 A plausibly has a similar biosynthetic origin to that of other thiazolyl peptide antibiotics such as nosiheptide and micrococcin.
Asunto(s)
Antibacterianos/química , Proteínas Bacterianas/biosíntesis , Péptidos Cíclicos/química , Inhibidores de la Síntesis de la Proteína/química , Actinomycetales/metabolismo , Secuencia de Aminoácidos , Aminoácidos/análisis , Antibacterianos/farmacología , Bacterias Anaerobias/efectos de los fármacos , Fenómenos Químicos , Química Física , Cromatografía de Gases y Espectrometría de Masas , Bacterias Grampositivas/efectos de los fármacos , Concentración de Iones de Hidrógeno , Hidrólisis , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Estructura Molecular , Peso Molecular , Péptidos/química , Péptidos/farmacología , Péptidos Cíclicos/farmacología , Inhibidores de la Síntesis de la Proteína/farmacología , Espectrometría de Masa Bombardeada por Átomos Veloces , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
1,5-Anhydro-3-O-benzyl-2,6-dideoxy-4-O-(3,4-di-O-benzyl-2,6-dideoxy-beta -D- arabino-hexopyranosyl)-D-arabino-hex-1-enitol (17), which corresponds to the B-C fragment of various orthosomycins, was prepared from phenyl 2,3-di-O-benzyl-6-deoxy-4-O-(3,4-di-O-benzyl-2,6-dideoxy- beta-D-arabino-hexopyranosyl)-1-thio-beta-D-glucopyranoside (16) by reductive lithiation. The synthesis of 16 involved a stereoselective coupling of phenyl 2,3-di-O-benzyl-6-deoxy-1-thio-beta-D-glucopyranoside (9) and 1,2-di-O-acetyl-3,4-di-O-benzyl-6-deoxy-beta-D-glucopyranose (14) followed by deoxygenation at C-2'. Glycosylation of methyl 2-O-benzyl-6- deoxy-4-O-methyl-beta-D-galactopyranoside (25) with 3,4,6-tri-O-acetyl-2-deoxy- 2-phthalimido-beta-D-glucopyranosyl trichloroacetimidate, followed by deamination at C-2', led stereospecifically to methyl 2-O-benzyl-6-deoxy-4-O-methyl-3-O-(3,4,6-tri-O-acetyl-2-deoxy-beta-D-ara bino- hexopyranosyl)-beta-D-galactopyranoside (26). The 2-deoxy unit of 26 was then modified by consecutive axial introduction of a C-Me group at position 3', protection of HO-3', and deoxygenation at C-6', in order to obtain methyl 3-O-(3-O-benzoyl-2,6-dideoxy-3-C-methyl-beta-D-arabino-hexopyranosyl)-2- O- benzyl-6-deoxy-4-O-methyl-beta-D-galactopyranoside (39), which corresponds to the D-E fragment of orthosomycins. A glycosyloxyselenation-oxidation-elimination sequence was performed on 39 and either 1,5-anhydro-3,4-di-O-benzyl-2,6- dideoxy-D-arabino-hex-1-enitol (40) or 1,5-anhydro-3-O-benzyl-2,6-dideoxy-4-O-(3,4-di-O-benzyl-2,6- dideoxy-beta-D-arabino-hexopyranosyl)-D-arabino-hex-1-enitol (17) to give the C-D-E tri-and B-C-D-E tetrasaccharide fragments, respectively. Each fragment contained the spiro-ortholactone junction with an (R) configuration at the anomeric carbon atom of the C-unit.
Asunto(s)
Antibacterianos/síntesis química , Oligosacáridos/síntesis química , Secuencia de Carbohidratos , Fenómenos Químicos , Química , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Estructura Molecular , Trisacáridos/síntesis químicaRESUMEN
N-Nitrosodiethanolamine metabolism was studied in order to clarify the mechanism(s) by which this compound elicits its carcinogenic effect. Samples of 24 h urine from rats given a single dose of N-nitrosodiethanolamine were collected. Gas chromatographic thermal energy analyses showed the presence of only one compound containing the nitroso moiety besides N-nitrosodiethanolamine. This compound was identified as the acidic derivative N-(2-hydroxyethyl)-N-carboxymethylnitrosamine by comparison with an authentic standard by means of gas chromatographic mass spectrometric analysis of the trimethylsilyl or pentafluorobenzyl esters. The amount of N-(2-hydroxyethyl)-N-carboxymethylnitrosamine excreted in the 24 h urine was about 6% of the N-nitrosodiethanolamine administered.