Lagunamycin, a novel 5-lipoxygenase inhibitor. II. Structural studies.
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Anti-Bacterial Agents↗
Biomedical subjects
T Oki
Publications and source records attributed to T Oki.
Antifungal activities of pradimicin derivatives modified at C4'-amino group.
In order to explore potent derivatives of pradimicins (PRMs), modification of their C4'-amino group was carried out. 4'-N-Cyano (1,2), 4'-deamino-4'-nitroguanidino (4), 4'-deamino-4'-ureido (7-9) and 4'-deamino-4'-thioureido (10) derivatives were synthesized by trimethylsilylation of PRMs A and C, followed by condensation with appropriate reagents. 4'-Deamino-4'-guanidino (5) and 4'-deamino-4'-amidino (6) derivatives were synthesized by catalytic hydrogenation of 4 and 2, respectively. 4'-N-Nitroso derivative 3 was prepared by treatment of PRM A with nitrous acid. Among these compounds, the 4'-N-cyano derivative of PRM C (2) exhibited in vitro and in vivo antifungal activities comparable to the parent compounds together with good water-solubility.
Animals↗
Angelmicins, new inhibitors of oncogenic src signal transduction.
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3T3 Cells↗
Synthesis and antifungal activity of pradimicin derivatives. Modifications on the aglycone part.
Synthesis and antifungal activity of pradimicin analogs modified on the aglycone part is described. Upon modification studies at various sites of the aglycone part using pradimicin A (PRM A), C-11 position was found to be the sole site to be modified without loosing antifungal activity. Further modification studies at C-11 position were carried out with 11-OH derivative of pradimicin T1 (PRM T1) because of its easy availability. Among the compounds prepared, 11-demethoxy derivative of PRM A (12) and 11-O-ethyl (13) and 11-O-fluoroethyl (14) derivatives of PRM T1 showed promising antifungal activity comparable to that of PRM A.
Antibiotics, Antineoplastic↗
Studies on the mode of antifungal action of pradimicin antibiotics. I. Lectin-mimic binding of BMY-28864 to yeast mannan in the presence of calcium.
BMY-28864 (BMS-181184), a water-soluble pradimicin derivative, specifically bound on the yeast cell surface in the presence of calcium, which was considered to be the initial step that triggered chain reactions leading to the fungicidal action. Close cause-effect relationships of the cell wall binding of BMY-28864 with its antifungal activity and potassium leakage induction were observed by Candida albicans and Saccharomyces cerevisiae in the presence and absence of calcium. Using mannan and methyl alpha-D-mannopyranoside as specific sugars, the mode of binding of BMY-28864 to sugar was examined in vitro in the presence of calcium. Quantitative component analysis revealed that the precipitate of BMY-28864 with methyl alpha-D-mannopyranoside and calcium was a ternary complex possessing a molar component ratio of 2.1:4.3:1.0. These findings altogether proved that BMY-28864, although not protein, recognized specific sugars such as mannose in the same manner as lectin, and that the ternary complex formation of BMY-28864 with specific sugar and calcium was the first step for expression of the selective antifungal action of the pradimicin.
Adsorption↗
Microbial modification of pradimicins at C-11 leading to 11-O-demethyl- and 11-O-L-xylosylpradimicins A and FA-1.
In a screen of pradimicin-nonproducing mutants derived from Actinomadura verrucosospora subsp. neohibisca R103-3, we found a strain capable of producing 11-hydroxyl analogs of pradimicins A and FA-1, designated pradimicins H and FH, respectively. Feeding of pradimicins H and FH to growing cultures of an actinomycete strain AA3798 produced 11-O-L-xylosylpradimicins H and FH, respectively. These 11-O-L-xylosylpradimicins had a broad spectrum of antifungal activity and demonstrated in vivo efficacies against Candida albicans in mice.
Actinomyces↗
New antiviral antibiotics, kistamicins A and B. I. Taxonomy, production, isolation, physico-chemical properties and biological activities.
A new strain of Microtetraspora parvosata subsp. kistnae subsp. nov. (ATCC 55076) was found to produce new antiviral antibiotics, designated kistamicins A and B. These antibiotics exhibited activity against influenza virus type A and moderate activity against Gram-positive bacteria.
Actinomycetales↗
New antiviral antibiotics, kistamicins A and B. II. Structure determination.
The structures of antiviral antibiotics kistamicins A and B have been determined by a combination of chemical degradation and spectral analysis. They are commonly composed of D-tyrosine, 3,5-dihydrophenylglycine, a biphenyl ether bis-amino acid, and a diphenyl substituted indole tris-amino acid, forming a tricyclic ring structure. Kistamicin B possessed a phenethylamide at the amino terminal of kistamicin A. They are structurally related to the nuclei of the vancomycin group antibiotics particularly to antibiotic complestatin.
Amino Acid Sequence↗
Nitrosoxacins A, B and C, new 5-lipoxygenase inhibitors.
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Hydroxylamines↗
Epocarbazolins A and B, novel 5-lipoxygenase inhibitors. Taxonomy, fermentation, isolation, structures and biological activities.
New 5-lipoxygenase inhibitors, designated epocarbazolins A and B, were isolated from the culture broth of Streptomyces anulatus T688-8. These compounds showed potent rat 5-lipoxygenase inhibitory activity with weak antibacterial activity. Structural studies revealed that epocarbazolins are new carbazole antibiotics having a novel substitution pattern and an epoxide in the side chain.
Animals↗
BMS-181184, a new pradimicin derivative. Screening, taxonomy, directed biosynthesis, isolation and characterization.
BMS-181184 is a new semisynthetic pradimicin derivative with a broad-spectrum antifungal activity. In a search for actinomycetes producing BMS-181184, 4 strains of Actinomadura sp. isolated from soil samples were found to produce the antibiotic under conditions of directed biosynthesis. Among them, Actinomadura sp. AB1236 proved most useful in the production of BMS-181184 when fermented in a medium containing D-serine and D-cycloserine. A minor product isolated from the broth of strain AB1236 was identified as the dexylosyl analog of BMS-181184, which was also obtained by acid hydrolysis of BMS-181184.
Actinomycetales↗
Pradimicins L and FL: new pradimicin congeners from Actinomadura verrucosospora subsp. neohibisca.
Pradimicin L, a new congener of pradimicin A having the D-glucosyl-D-thomosamine moiety at the C-5 position, was isolated from Actinomadura verrucosospora subsp. neohibisca subsp. nov. The structure of pradimicin L was deduced to be N-[[(5S,6S)-5-O-[4,6-dideoxy-4-(methylamino)-3-O-(beta-D-glucopyranosyl) - beta-D-galactopyranosyl]-5,6,8,13-tetrahydro-1,5,6,9,14-pentahydroxy-11- methoxy-3-methyl-8,13-dioxobenzo[a]naphthacene-2-yl]carbonyl ]-D-alanine by MS and NMR spectrometry and degradation studies. Pradimicin FL which has the D-serine moiety instead of D-alanine was produced by directed biosynthesis in D-serine-supplemented medium. Pradimicins L and FL have a broad spectrum of in vitro antifungal activity. Pradimicin L was equiactive to pradimicin A and pradimicin FL was more active than pradimicin L.
Actinomycetaceae↗
Pradimicins FS and FB, new pradimicin analogs: directed production, structures and biological activities.
Exogenous addition of D-serine to Actinomadura spinosa AA0851 resulted in directed production of pradimicin FS, a new D-serine analog of pradimicin S, together with pradimicin FB. Pradimicin FS was produced in higher yields by derivation of ferrous sulfate-resistant strains from strain AA0851. Pradimicin FB, a minor product, was identified as deglucosylpradimicin FL. Pradimicin FS was equivalent to pradimicin S in syncytium formation inhibition activity and in vitro and in vivo antifungal activities.
Actinomycetaceae↗
Pradimicin S, a new pradimicin analog. II. Isolation and structure elucidation.
Pradimicin S was isolated from the culture filtrate of Actinomadura spinosa AA0851. NMR and MS analyses proved that pradimicin S is the 3'-O-(3''-O-sulfo-beta-D-glucopyranosyl) analog of pradimicin A, a new member of the pradimicin family of antibiotics. Stereochemical assignment was made by correlating pradimicin S with pradimicin L.
Actinomycetaceae↗
Biosynthesis of the pradimicin family of antibiotics. I. Generation and selection of pradimicin-nonproducing mutants.
Germinated spores of Actinomadura verrucosospora subsp. neohibisca E-40, a high pradimicins producer, were mutagenized by N-methyl-N'-nitro-N-nitrosoguanidine and/or UV treatment. Thirty-seven mutants which did not produce pradimicin were selected to test for cosynthesis ability, and classified into nine classes. On the basis of their cosynthesis ability and bioconversion results, we concluded that strain JN-213 (class III) was a true converter and that strains JN-219 (class IV), JN-47 (class V) and JNU-46 (class VI) were secretors accumulating biosynthetic intermediates of pradimicin, and that strains JN-59 (class VII), JN-58 (class VIII) and JN-207 (class IX) were producers of shunt metabolites of pradimicin biosynthesis. TLC and HPLC analyses of the fermentation broths of individual strains showed that 8 new compounds were produced along with pradinone I, pradimicinone I, 11-O-demethylpradimicinone II and 7-O-methylpradimicinone II.
Actinomycetaceae↗
Biosynthesis of the pradimicin family of antibiotics. II. Fermentation, isolation and structure determination of metabolites associated with the pradimicins biosynthesis.
Ten metabolites produced by 4 mutants derived from Actinomadura verrucosospora subsp. neohibisca E-40, a high pradimicins producer, were isolated and their structures were determined. Strain JN-219 produced 3 novel analogs of the pradimicin A aglycone, i.e. 11-O-demethyl-7-methoxypradinone II and 11-O-demethylpradinones I and II together with a known aglycone analog, pradinone I, while the metabolites from strain JN-47 were determined to be 2 new aglycone analogs, 11-O-demethylpradimicinone I and 11-O-demethyl-7-methoxypradimicinone II and a known aglycone analog, 11-O-demethylpradimicinone II (11dM-PMN II). Products of strain JN-207 were identified as 11-O-demethyl-6-deoxypradinone I and 11dM-PMN II. Interestingly, a new pradimicin analog, 7-hydroxypradimicin A was isolated from strain JN-58 together with a new aglycone analog, pradimicinone II and 11dM-PMN II. None of these metabolites showed antifungal activity.
Actinomycetaceae↗
Biosynthesis of the pradimicin family of antibiotics. III. Biosynthetic pathway of both pradimicins and benanomicins.
The biosynthetic pathway of the pradimicin-benanomicin family of antibiotics was investigated by using sinefungin and blocked mutants derived from Actinomadura verrucosospora subsp. neohibisca E-40 (a high pradimicin producer) or Actinomadura sp. AB1236 (a benanomicin producer). Addition of sinefungin to strain E-40, pradimicin A aglycone-producing mutant or strain AB1236 inhibited the formation of 11-O-demethyl-7-methoxypradinone II (11dM-7M-PN II), resulting in the accumulation of 11-O-demethylpradimicinone II and pradimicinone II. By feeding pradimicin A aglycone and its analogs to mutants blocked early in pradimicin or benanomicin biosynthesis, the following results were obtained: 11-O-demethylpradinone II, 11dM-7M-PN II 11-O-demethylpradinone I, 11-O-demethylpradimicinone I and pradimicinone I were converted to pradimicin A or benanomicin A; the remaining 6 aglycone analogs were not incorporated into the antibiotics. Pradimicin B, dexylosylpradimicin C and dexylosylbenanomicin A were converted to pradimicin A, pradimicin C and benanomicin A, respectively. A biosynthetic pathway for the antibiotics is proposed.
Actinomycetales↗
Studies on the mode of antifungal action of pradimicin antibiotics. II. D-mannopyranoside-binding site and calcium-binding site.
Based on the structure-activity relationship data of BMY-28864 and related pradimicin derivatives, the calcium salt-forming ability and the D-mannopyranoside-specific visible absorption maximum shift of BMY-28864 were analysed in the ternary complex formation of BMY-28864 with D-mannopyranoside and calcium. The free C-18 carboxyl group of BMY-28864 was proved to be the sole site for binding to calcium, while no hydroxyl groups of the aglycone were involved in calcium salt formation. The stereospecific D-mannopyranoside-recognizing ability of BMY-28864 was completely abolished by removal of the C-5 disaccharide moiety, and, more particularly, of the C-5 thomosamine moiety. Close relationship of these findings with the antifungal action was also supported by the in vitro antifungal assay and the potassium leakage induction test.
Anthracyclines↗