ABSTRACT
1,10-Di-0-acetyl-2,3,4,6,7,8,9-heptadeoxy-2,6-bis(2, 4-dinitrophenylamino)-L-lyxo-decopyranose (7) and -D-ribo-decopyranose (8) have been prepared from methyl 2-acetamido-2,3,4,6-tetradeoxy-6-nitro-alpha-D-erythro-hexopyranoside via a nitro aldol reaction with 4-[(tetrahydropyranyl)oxy]butanal in the presence of cesium fluoride, and their configurations at C-6 have been established by conversion of the precursor of 8, namely, methyl 2,6-diacetamido-10-O-acetyl-2,3,4,6,7,8,9-heptadeoxy-alpha-D - ribo-decopyranoside, into the known methyl 2,6-diacetamido-2,3,4,6,7,8,9,10-octadeoxy-alpha-D-ribo-d ecopyranoside. The title fortimicin A derivatives, 7'-(3-hydroxypropyl)fortimicin A and 6'-epifortimicin A, have been synthesized by condensation of compound 7 and 8, respectively, with 2,5-di-O-benzoyl-1,4-bis[N-(methoxycarbonyl)]fortamine B, followed by deprotection and introduction of a glycyl group. Their antimicrobial activities have been found to be weak compared to that of fortimicin A.
Subject(s)
Aminoglycosides , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Indicators and Reagents , Microbial Sensitivity Tests , Optical Rotation , Structure-Activity RelationshipABSTRACT
Three methods have been developed for measuring pseudo-alpha- and pseudo-beta-DL-glucose (pseudo-beta-D-glucose), synthetic compounds in which the ring oxygens of alpha- and beta-DL-glucose (beta-D-glucose) have been replaced by a methylene group. Moderate sensitivity in the determination of these pseudo-glucoses dissolved in human serum was obtained by GLC (0.1 nmol) and HPLC (0.5 nmol). The colorimetric determination with glucose 2-oxidase, peroxidase, and 2,2'-azino-di-(3-ethylbenzothiazoline-6-sulfonic acid) was satisfactory for the assay of pseudo-alpha- and pseudo-beta-DL-glucose (respective sensitivities: 25 and 5 nmol). The addition of hexokinase to the colorimetric assay system made it possible to eliminate glucose present in the sample, such as serum, and the remaining pseudo-alpha- or pseudo-beta-DL-glucose in the sample solution could then be measured by a colorimetric method using glucose 2-oxidase. The methods described can be used for biochemical studies involving pseudo-alpha- and pseudo-beta-DL-glucose.
Subject(s)
Glucose/analogs & derivatives , Chromatography, Gas , Chromatography, High Pressure Liquid , Colorimetry , Glucose/analysis , Glucose Oxidase , Humans , StereoisomerismABSTRACT
Pseudo-alpha- and pseudo-beta-DL-glucose, the isomers of 5-hydroxymethyl-1,2,3,4-cyclohexanetetrol with alpha-gluco and beta-gluco configurations, were used as synthetic analogs of glucose anomers to study the mechanism of glucose-stimulated insulin release by pancreatic islets. Neither isomer was phosphorylated by liver glucokinase nor stimulated insulin release from islets. Incubation of islets with pseudo-alpha-DL-glucose resulted in a considerable accumulation of the glucose analog, probably the D form, in islets. The alpha-isomer, but not the beta-isomer, inhibited both glucose-stimulated insulin release (44% inhibition at 20 mM) and islet glucokinase activity (36% inhibition at 20 mM) in a concentration-dependent manner and to a comparable degree. These results strongly suggest that the inhibition of glucose-stimulated insulin release by pseudo-alpha-DL-glucose is due to the inhibition of islet glucokinase by the glucose analog, providing additional evidence for the essential role of islet glucokinase in glucose-stimulated insulin release.
Subject(s)
Glucokinase/antagonists & inhibitors , Glucose/analogs & derivatives , Glucose/pharmacology , Insulin/metabolism , Islets of Langerhans/metabolism , Animals , Glucokinase/metabolism , Glucose/metabolism , Hexokinase/metabolism , Insulin Secretion , Islets of Langerhans/drug effects , Islets of Langerhans/enzymology , Kinetics , Liver/enzymology , Male , Rats , Rats, Inbred StrainsABSTRACT
Fourteen (2-chloroethyl)nitrosourea congeners of L-amino acid amides have been synthesized as potential antineoplastic agents. Almost all the congeners tested were found to be highly active against experimental leukemia L1210 in mice. The chemical decomposition rates of the congeners were measured in a buffered solution (pH 7.4) at 37 degrees C. Acute toxicities of some of the congeners were determined for mice. The congener of sarcosinamide shows the longest half-life (T0.5 = 329.7 min) and the lowest toxicity, LD50 = 392.0 mg/kg (ip) and 426.6 mg/kg (iv), in this series.
Subject(s)
Antineoplastic Agents/chemical synthesis , Nitrosourea Compounds/chemical synthesis , Amino Acids/chemical synthesis , Amino Acids/pharmacology , Animals , Chemical Phenomena , Chemistry , Lethal Dose 50 , Leukemia L1210/drug therapy , Male , Mice , Nitrosourea Compounds/pharmacology , Nitrosourea Compounds/toxicityABSTRACT
Chlorination of antibiotic fortimicin A with triphenylphosphine and carbon tetrachloride has been attempted, and 2-chloro-, 2,5-dichloro-, and 2-chloro-4-ene derivatives have been obtained. Successive dehalogenation of the chlorinated fortimicins A with tributylstannane gave the corresponding deoxyfortimicins A. Among five deoxyfortimicins A, 2-deoxyfortimicin A exhibits improved antimicrobial activity, compared to the parent fortimicin A.
Subject(s)
Anti-Bacterial Agents , Aminoglycosides/pharmacology , Bacteria/drug effects , Chemical Phenomena , Chemistry , Drug Resistance, Microbial , Molecular Conformation , Structure-Activity RelationshipSubject(s)
Anti-Bacterial Agents , Aminoglycosides , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Chemical Phenomena , Chemistry , Dibekacin/analogs & derivatives , Dibekacin/pharmacology , Drug Resistance, Microbial , Inositol/analogs & derivatives , Magnetic Resonance Spectroscopy , Models, Chemical , Molecular Conformation , Neomycin/analogs & derivatives , Neomycin/pharmacology , Structure-Activity RelationshipABSTRACT
N-(2-Chloroethyl)-N-nitrosocarbamoyl derivatives of glycosylamines have been prepared. Six N-(2-chloroethyl)-N-nitrosoureas, including three disaccharide derivatives, were submitted to a determination of antitumor activity. All the compounds tested exhibited strong antitumor activity against leukemia L1210 in mice.
Subject(s)
Antineoplastic Agents/chemical synthesis , Nitrosourea Compounds/chemical synthesis , Animals , Antineoplastic Agents/therapeutic use , Chemical Phenomena , Chemistry , Leukemia L1210/drug therapy , Male , Mice , Mice, Inbred Strains , Nitrosourea Compounds/pharmacology , Nitrosourea Compounds/therapeutic useABSTRACT
The aminocyclitol antibiotic neamine has been modified by changing the configuration of one or two hydroxyl groups of the aminocyclitol moiety to elucidate the relationship between configuration and antimicrobial activity. 5-Epi-, 6-epi-, and 5,6-diepineamine have been prepared and their antimicrobial activity has been determined against several micro-organisms.
Subject(s)
Neomycin/analogs & derivatives , Microbial Sensitivity Tests , Neomycin/chemical synthesis , Structure-Activity RelationshipABSTRACT
The aminocyclitol antibiotic neamine has been modified chemically by removing one or two hydroxyl groups from the 2-deoxystreptamine moiety to give 5- and 6- deoxyneamines (5 and 10), as well as 5,6-dideoxyneamine (15). Their antimicrobial activities were determined against several microorganisms, including kanamycin-resistant strains.
Subject(s)
Neomycin/analogs & derivatives , Bacillus subtilis/drug effects , Escherichia coli/drug effects , Klebsiella pneumoniae/drug effects , Magnetic Resonance Spectroscopy , Methods , Microbial Sensitivity Tests , Mycobacterium/drug effects , Neomycin/chemical synthesis , Neomycin/pharmacology , Optical Rotation , Species Specificity , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
The aminocyclitol antibiotic neamine has been chemically modified at the hydroxyl group on C-6 of the 2-deoxystrepatamine moiety. The partially acetylated neamine derivatives, 6,3,4-tri-O-acetyl- (3) and 5,3-57,4-tri-O-acetyl-1,3,2,6-tetra-N-(ethoxycarbonyl)neamine (4), were prepared by random hydrolysis of the 5,6-O-ethoxyethylidene derivative (2), followed by chromatographic purification. Condensation of 4 and 2,3,5-tri-O-benzoyl-D-ribofuranosyl chloride led to 6-O-(beta-D-ribonfuranosyl)neamine (7). Analogous condensation of 4 with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide or 2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranosyl bromide afforded the corresponding 6-O-(D-hexopyranosyl)neamines.
