Modelling basic features of specificity in DNA-aureolic acid-derived antibiotic interactions.
(1/9)
The nonintercalative groove binding of a simplified model of olivomycin, to sequences d(CGCGCGC)2, d(TATATAT)2, and d(CICICIC)2 is investigated. A significant preference is displayed for the minor groove of the d(CG) sequence. This is due predominantly to the formation of H-bonds between the hydroxyl groups on the aglycone of the drug and the 2-amino group of the central guanine of the oligonucleotide. (+info)
Investigations into the sequence-selective binding of mithramycin and related ligands to DNA.
(2/9)
The preferred binding sites for mithramycin on four different DNA fragments have been investigated by DNAase I footprinting. Sites containing at least two contiguous GC base pairs are protected by the antibiotic, the preferred binding site consisting of the dinucleotide step GpG (or CpC). Related antibiotics chromomycin and olivomycin produce similar, but not identical footprinting patterns suggesting that they can recognize other sequences as well. All three antibiotics induce enhanced rates of enzyme cleavage at regions flanking some of their binding sites. These effects are generally observed in runs of A and T and are attributed to DNA structural variations induced in the vicinity of the ligand binding site. The reaction of dimethylsulphate with N7 of guanine was modified by the presence of mithramycin so that we cannot exclude the possibility that these antibiotics bind to DNA via the major groove. (+info)
Species-specific differences in the toxicity and mutagenicity of the anticancer drugs mithramycin, chromomycin A3, and olivomycin.
(3/9)
Three structurally related anticancer drugs, mithramycin, chromomycin A3, and olivomycin, exhibited large differences (greater than 100-fold) in their toxicity towards cultured cells from various species. These differences are species related, as all cell lines from any one species showed similar sensitivity to the three drugs. Of the three species examined, namely, human, mouse, and Chinese hamster, human cells were found to be most sensitive to these drugs. However, no significant difference in toxicity was observed between normal human diploid fibroblasts and heteroploid cell lines established from tumors. The above drugs were found to induce mutants at the hypoxanthine-guanine phosphoribosyl-transferase locus (i.e., resistance to 6-thioguanine) and produced DNA strand breaks, in a dose-dependent manner, in cells from all three species. However, the concentrations of these drugs which produced similar mutagenic or DNA strand break responses differed greatly for cells from the three species, and a good correlation was observed between the toxic and the mutagenic concentrations of these drugs for cells from the three species examined. These studies provide strong evidence that the toxic and mutagenic concentrations of different substances could differ greatly between cells from human and other species and indicate that the results of such studies cannot always be extrapolated from animal to human situations. It is suggested that a knowledge of the relative toxicity of any chemical towards cultured cells from human versus test animal should prove of value in extrapolating the results from animal systems to humans. (+info)
NMR studies of chromomycins, olivomycins, and their derivatives.
(4/9)
Detailed studies on the 13C and 1H NMR spectra of chromomycins A2 and A3, olivomycins A and B, and their derivatives clarified the assignment of many signals which had been unassigned or erroneously reported in the literatures. The revised assignments for chromomycin A3 and olivomycin A include the assignment of a key 13C signal used to discuss the saccharide linkage in question. Structure analyses based on the revised assignments support the alpha,1----3-bond between components of the disaccharide moiety in the molecules. Some general information useful for structure analysis of saccharides is also reported. (+info)
New aureolic acid antibiotics. II. Structure determination.
(5/9)
Structure determination using NMR spectroscopy of new aureolic acid analogues, demethylchromomycins A2 and A3 and demethylolivomycins A and B produced by Streptomyces aburaviensis PA-39856, is described. (+info)
Development of enzyme immunoassay for chromomycin A3 and olivomycin using beta-D-galactosidase as a label.
(6/9)
An antibody specific for chromomycin A3 (CHM; byname, toyomycin) was produced in sufficiently high titer in rabbits by immunization with a CHM-bovine serum albumin conjugate, prepared using diazotized p-aminobenzoic acid as a coupling agent. CHM was also coupled with beta-D-galactosidase (EC 3.2.1.23) using diazotized m-aminobenzoic acid and was used as a tracer. With these reagents, a double-antibody enzyme immunoassay for CHM and for the CHM homologue olivomycin was developed which was highly sensitive and accurate enough to measure as little as 10 and 50 pg of each drug per assay tube, respectively. The enzyme immunoassay did not cross-react with mithramycin and drugs commonly used with CHM in combination chemotherapy for cancer treatment. Using this assay, drug levels were easily determined in blood and urine of rats following administration of CHM in a single dose of 2.0 mg/kg i.v. The sensitivity and specificity of the enzyme immunoassay for CHM and olivomycin should provide a valuable new tool for use in pharmacokinetic and toxicity studies of these drugs. (+info)
Antibiotic induced electrophoretic mobility shifts of DNA restriction fragments.
(7/9)
Several antibiotics, netropsin, distamycin A, actinomycin D, Hoechst 33258 and olivomycin, which demonstrate base specificity in their DNA binding properties have been found to alter the electrophoretic mobility of DNA restriction fragments in native polyacrylamide gels. The antibiotics mostly reduced the migration of larger DNA fragments, but netropsin and Hoechst 33258 were observed to increase the migration rate of several DNA fragments of intermediate size. DNA fragments of similar molecular weight which comigrate as a single gel band can at times be separated as the result of differential mobility shifts promoted by antibiotic DNA complex formations. (+info)
Biotransformation of antitumor agents by a strain of Whetzelinia sclerotiorum.
(8/9)
Antitumor antibiotics of the olivomycin and chromomycin class were transformed when incubated with a culture of Whetzelinia sclerotiorum. The products, when purified by counter-current distribution and column chromatography, were shown, by their physical properties, to be the deacylated analogues. (+info)