ABSTRACT
The new pluramycin-type antibiotics pluraflavin A, C43H54N2O14, pluraflavin B, C43H56N2O15, and pluraflavin E, C36H41NO14 were isolated from cultures of the Saccharothrix species DSM 12931. The structures of the novel compounds were elucidated with the aid of 2D NMR and mass spectrometric investigations. The characteristic structural element of pluraflavins A and B is an additional 4-epi-vancosamine unit at position 13 of the anthraquinone-gamma-pyrone ring system. Pluraflavin E has a carboxyl group in this position. Pluraflavin A has a reactive dimethyl epoxide side chain at position 2 of the anthraquinone-gamma-pyrone aglycon, which may explain the high activity of the antibiotic. The outstanding biological characteristic of pluraflavin A is its powerful, organ-dependent cytostatic action: the IC50 in the colon carcinoma proliferation assay is in the subnanomolar range.
Subject(s)
Actinomycetales/metabolism , Anthraquinones/isolation & purification , Anthraquinones/metabolism , Anthraquinones/pharmacology , Antibiotics, Antineoplastic/biosynthesis , Antibiotics, Antineoplastic/isolation & purification , Cell Division/drug effects , Actinomycetales/growth & development , Anthraquinones/chemistry , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Culture Media , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry/methods , Molecular Structure , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Anthraquinones/chemistry , Enzyme Inhibitors/chemistry , Phosphotransferases/antagonists & inhibitors , Streptomyces/metabolism , Anthraquinones/chemical synthesis , Anthraquinones/isolation & purification , Antiporters , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Cyclization , Enzyme Inhibitors/isolation & purification , Magnetic Resonance Spectroscopy , Methylation , Molecular Conformation , Monosaccharide Transport Proteins , Spectrophotometry, Ultraviolet , Streptomyces/chemistryABSTRACT
The C7 hydroxy group of cytotoxic epothilone A was selectively oxidized using PDC. A selective oxidation of the C3 hydroxy group was accomplished with Me2S/(PhCO2)2 after in situ protection of C7-OH. Reduction of epothilone A or of a C5, C7 dioxo derivative with NaBH4 proceeded at the C5 carbonyl group. Oxidation and hydrogenation of the C16-C17 double bond proved to be difficult but it was easily cleaved with ozone and the resulting keto derivative was transformed to epothilone analogs with different side chains.
Subject(s)
Antineoplastic Agents/chemical synthesis , Epothilones , Epoxy Compounds/chemical synthesis , Thiazoles/chemical synthesis , Fermentation , Oxidation-ReductionABSTRACT
An antifungal activity, ratjadon, was detected in the culture broth of Sorangium cellulosum (Myxococcales) strain So ce360. The metabolite was quantitatively bound to the adsorber resin XAD-16, which was added to the medium at the beginning of the fermentation. The antibiotic spectrum was narrow, but some important phytopathogenic fungi, especially species of Oomycetes, were inhibited at very low concentrations.
Subject(s)
Antifungal Agents/isolation & purification , Animals , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Fermentation , HeLa Cells/drug effects , Humans , Mice , Microbial Sensitivity Tests , Myxococcales/metabolism , Pyrans/chemistry , Pyrans/isolation & purification , Pyrans/pharmacologyABSTRACT
New antibiotics were isolated from the culture broth of the myxobacterium, Sorangium cellulosum, strain So ce 678. The antibiotics were active against Gram-positive bacteria and mammalian cells. They were named tartrolon A and B. Tartrolon B contains a boron atom. The boron binding region of tartrolon is identical with that of boromycin and aplasmomycin.
Subject(s)
Anti-Bacterial Agents/biosynthesis , Anti-Bacterial Agents/pharmacology , Boron Compounds/metabolism , Boron Compounds/pharmacology , Myxococcales/metabolism , Borates/metabolism , Borates/pharmacology , Chemical Phenomena , Chemistry, Physical , DNA, Bacterial/biosynthesis , DNA, Bacterial/drug effects , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/metabolism , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/metabolism , Lactones/metabolism , Lactones/pharmacology , Microbial Sensitivity Tests , Myxococcales/chemistry , RNA, Bacterial/biosynthesis , RNA, Bacterial/drug effects , Staphylococcus aureus/drug effects , Staphylococcus aureus/metabolismABSTRACT
The photoreactive ganglioside derivative N-diazirinyl-lyso-GM1 was incorporated into liposomes and calf brain microsomes. After photoactivation at 350 nm it was found to dimerize with phospholipids such as phosphatidylcholine and phosphatidylserine and with cholesterol. The predominant covalent reaction product, however, was the alcohol, resulting from the reaction with water. It amounted to about 45% of the covalent reaction products in calf brain microsomes and to about 58% in pure phosphatidylcholine liposomes. Based on the temperature dependence of the photoreaction of N-diazirinyl-lyso-GM1 in liposomes consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphoryl-choline or 1,2-distearoyl-sn-glycero- 3-phosphorylcholine and on affinity labeling experiments with cholera toxin we propose that the predominant reaction of N-diazirinyl-lyso-GM1 with water is due to the presence of water within the hydrophobic core of artificial and biological membranes.
