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FERMENTATION, ISOLATION, PHYSICO-CHEMICAL PROPERTIES AND BIOLOGICAL ACTIVITIES
MITSUHIRO UENO, MASATOMI IIJIMA, TORU MASUDA, NAOKO KINOSHITA, HIRONOB ...
1992 Volume 45 Issue 12 Pages
1819-1826
Published: December 25, 1992
Released on J-STAGE: April 19, 2006
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In the course of screening for immunomodulators inhibiting the mixed lymphocyte culture reaction (MLCR), we found a novel immunosuppressant, dethymicin in mycelium of
Amycolatopsis mediterranei MI710-51F6. From physico-chemical properties and biological activity it is different from immunosuppressants produced by microorganisms such as cyclosporins, FK506 and rapamycin. It inhibited immune responses
in vitro and
in vivo, and prolonged skin allograft in rats.
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DON E. HARPER, DANNY R. WELCH
1992 Volume 45 Issue 12 Pages
1827-1836
Published: December 25, 1992
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In screening of actinomycetes for structures with differential solid tumor activity,
Streptomyces griseoluteus, strain WS6724 was found to produce U-77863 and U-77864. U-77863 exhibited antiinvasive activity
in vitro in the membrane invasion culture system (MICS) and a dose-dependent antimetastatic activity
in vivo versus K1735-M2 and B16-F10 murine melanomas. The isolation, purification, and synthesis of both structures and biological activity is reported.
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OSAMU JOHDO, HIROSHI TONE, ROKURO OKAMOTO, AKIHIRO YOSHIMOTO, TOMIO TA ...
1992 Volume 45 Issue 12 Pages
1837-1847
Published: December 25, 1992
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Microbial 4-
O-methylation using a specific daunorubicin-blocked, nonproducing mutant provided the new anthracycline antibiotics 4-
O-methylbetaclamycin T, 4-
O-methylyellamycin A and 4-
O-methyl-13-hydroxyoxaunomycin, from which 4-
O-methyloxaunomycin and 4-
O-methyl-6-deoxyoxaunomycin were then prepared by further photochemical
N-demethylation. Antitumor activities
in vitro and
in vivo against L1210 cells were compared with those of their 4-
O-demethyl derivatives. It was found that all the 4-
O-methyl derivatives had a markedly reduced cytotoxicity
in vitro as compared with the 4-
O-demethyl compounds. However, some of them were endowed with a significantly improved antitumor activity
in vivo.
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AKIO MAEDA, KATSUKIYO YAZAWA, YUZURU MIKAMI, MASASHI ISHIBASHI, JUN'IC ...
1992 Volume 45 Issue 12 Pages
1848-1852
Published: December 25, 1992
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The producer of SO-075R1, a new anthracycline group antibiotic was identified as
Nocardia brasiliensis. SO-075R1 was active against Gram-positive bacteria, but not active against Gram-negative bacteria or fungi. All tested
Nocardia brasiliensis strains as well as the producer itself were resistant to SO-075R1, although four other pathogenic
Nocardia, i.e.
N. asteroides,
N. nova,
N. farcinica and
N. otitidiscaviarum were sensitive.
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I. DISCOVERY AND ISOLATION
ROBERT E. SCHWARTZ, DAVID F. SESIN, HENRY JOSHUA, KENNETH E. WILSON, A ...
1992 Volume 45 Issue 12 Pages
1853-1866
Published: December 25, 1992
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HPLC bioautography of the directed biosynthesis of
Zalerion arboricola led to the discovery of pneumocandin B
0 (L-688, 786), a new antifungal and anti-
Pneumocystis carinii lipopeptide. Isolation techniques were developed to separate this component from pneumocandin A
0 (L-671, 329) in fermentations of a mutant of
Zalerion arboricola. A number of related compounds were also isolated, which differ from pneurnocandins A
0 and B
0 in the hydroxylation patterns on the ornithine, homotyrosine, and proline.
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II. MODIFICATION OF PRODUCT SPECTRUM BY MUTATION AND MEDIUM MANIPULATION
PRAKASH S. MASUREKAR, JIMMY M. FOUNTOULAKIS, THOMAS C. HALLADA, MARGAR ...
1992 Volume 45 Issue 12 Pages
1867-1874
Published: December 25, 1992
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Zalerion arboricola ATCC 20868 produces pneumocandin A
0 (L-671, 329), a cyclic hexapeptide with a dimethylmyristic acid side chain. This compound has anti-candida and anti-pneumocystis activities. We were interested in looking for other related compounds produced by this organism. To facilitate this search, a simple medium (S2) composed of D-mannitol, peptonized milk, lactic acid, glycine, KH
2PO
4 and trace elements, which supported the production of a number of such compounds, was designed. For the isolation of mutants, either spores or growing mycelia were treated with
N-nitroso-
N-methylurethane or
N-methyl-
N'-nitro-
N-nitrosoguanidine and survivors were screened for changes in the product spectrum. From approximately 1, 500 survivors tested, 5 mutants were isolated. Mutants ATCC 20957, 74030, 20958 and 20988 exclusively produce various pneumocandins other than A
0. These compounds were active against
Candida and
Pneumocystis carinii. The yield of A
0 was found to be increased 2.5-fold over that of the parent in the fifth mutant, MF5415. Further medium studies indicated that the addition of soybean oil to S2 medium improved the yields. Subsequent development of another series of media containing Pharmamedia as a nitrogen source resulted in increase in production by 10--20-fold. Overall, these studies resulted in substantial improvement in the production of A
0 as well as discovery and/or facile production of 7 other related compounds.
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III. STRUCTURE ELUCIDATION
OTTO D. HENSENS, JERROLD M. LIESCH, DEBORAH L. ZINK, JACK L. SMITH, CA ...
1992 Volume 45 Issue 12 Pages
1875-1885
Published: December 25, 1992
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Pneumocandin B
0 (
6) and six related lipopeptides are antifungal and anti-
Pneumocystis carinii agents from mutants of
Zalerion arboricola, whose structures were determined mainly on the basis of spectroscopic analysis. They belong, along with pneumocandin A
0 (L-671, 329) previously isolated from these laboratories,
1) to the echinocandin class of antifungal agents. The product from base-catalyzed ring opening involving the hemiaminal position of the dihydroxyornithine residue of B
0, has been clearly defined as
6b. Modifications were limited to the 3-hydroxy-4-methylproline, 3, 4-dihydroxyhomotyrosine and 4, 5-dihydroxyornithine residues of pneumocandin A
0.
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IV. BIOLOGICAL EVALUATION OF NATURAL AND SEMISYNTHETIC PNEUMOCANDINS FOR ACTIVITY AGAINST Pneumocystis carinii AND Candida SPECIES
D. M. SCHMATZ, G. ABRUZZO, M. A. POWLES, D. C. MCFADDEN, J. M. BALKOVE ...
1992 Volume 45 Issue 12 Pages
1886-1891
Published: December 25, 1992
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A series of lipopeptide compounds co-produced during the fermentation of pneumocandin A
0 (L-671, 329) and related semisynthetic compounds were evaluated
in vivo against
Pneumocystis carinii pneumonia and systemic candidiasis. In addition, they were tested
in vitro against a panel of pathogenic
Candida species and in a
Candida membrane 1, 3-β-D-glucan synthesis assay. The results of these studies demonstrate that pneumocandin A
0 and pneumocandin B
0 (L-688, 786) are the most potent compounds when considering both antipneumocystis and anticandida activity. Other compounds in the series are selectively more potent against
P. carinii or
Candida albicans suggesting a diverging structure-activity relationship. Evaluation of these compounds for their ability to inhibit
C. albicans 1, 3-β-D-glucan synthesis
in vitro demonstrates that they inhibit this process. A positive correlation between 1, 3-β-D-glucan synthesis inhibition and
in vitro antifungal activity was also demonstrated for some of the pneumocandins.
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I. TAXONOMY, PRODUCTION, ISOLATION AND BIOLOGICAL ACTIVITY
J. SCOTT WELLS, JOSEPH O'SULLIVAN, CAROL AKLONIS, HELEN A. AX, ADRIENN ...
1992 Volume 45 Issue 12 Pages
1892-1898
Published: December 25, 1992
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A screen for antibiotics with activity against tetracycline-resistant microorganisms has led to the isolation of
Dactylosporangium sp. (ATCC 53693), a producer of several novel tetracycline derivatives. The major fermentation products, dactylocyclines A and B, were purified and MIC values determined against tetracycline-resistant and tetracycline-sensitive Gram-positive bacteria. The dactylocyclines represent the first naturally occuring tetracycline C2 amides which lack cross resistance with tetracycline.
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II. STRUCTURE ELUCIDATION
ADRIENNE A. TYMIAK, HELEN A. AX, MARK S. BOLGAR, ALICIA D. KAHLE, MICH ...
1992 Volume 45 Issue 12 Pages
1899-1906
Published: December 25, 1992
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Fermentation of
Dactylosporangium sp. (ATCC 53693) produces a mixture of tetracycline derivatives from which several related tetracycline glycosides, the dactylocyclines, were isolated and their structures determined. The most abundant glycoside in initial fermentations was found to be dactylocycline A. Each glycoside proved to be acid sensitive and readily hydrolyzed to a common aglycone, dactylocyclinone. While the aglycone was cross resistant with tetracycline, the dactylocyclines proved active against certain tetracycline-resistant organisms.
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III. ABSOLUTE STEREOCHEMISTRY OF THE DACTYLOCYCLINES
PRATIK V. DEVASTHALE, LESTER A. MITSCHER, HANUMAIAH TELIKEPALLI, DAVID ...
1992 Volume 45 Issue 12 Pages
1907-1913
Published: December 25, 1992
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The dactylocycline antibiotics were found through circular dichroism measurements, NMR spectroscopy and chemical transformations to possess the usual tetracycline family absolute configuration at carbons 4, 4a, 5a and 12a. The absolute stereochemistry about the C-6 carbon, however, was the reverse of that found with previously investigated tetracyclines.
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H. D. HOLLIS SHOWALTER, RICHARD H. BUNGE, JAMES C. FRENCH, TIMOTHY R. ...
1992 Volume 45 Issue 12 Pages
1914-1918
Published: December 25, 1992
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A practical process is described for the large-scale isolation of pentostatin, an adenosine deaminase inhibitor used clinically for the treatment of interferon-refractory hairy cell leukemia. The identities of minor components in the fermentation beer, including 2'-deoxyguanosine, are also reported.
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YOKO IKEDA, HIROSHI NAGANAWA, SHINICHI KONDO, TOMIO TAKEUCHI
1992 Volume 45 Issue 12 Pages
1919-1924
Published: December 25, 1992
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The biosynthesis of bellenamine was studied by feeding
13C and
15N labeled precursors to the synthetic medium culture of
Streptomyces nashvillensis MD743-GF4. The high degree of incorporation of D-[1-
13C]β-lysine indicated that it is a direct intermediate, while supplemented L-β-lysine repressed the production of bellenamine. [2-
13C]Glycine was well incorporated into the C-1' of the open-chain aldoaminal structure. All four nitrogens of bellenamine were derived from [
15NH
4]
2SO
4 present in the synthetic medium. In the addition of L-lysine and glycine, [
15NH
4]
2SO
4 was highly incorporated into CONH. The feeding experiments of
13C labeled acetates suggested that the D-β-lysine moiety was derived from L-lysine by catalysis of a new 2, 3-aminomutase, and L-lysine was biosynthesized from acetates via the TCA cycle and diaminopimelic acid pathway.
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YOKO IKEDA, HIROSHI NAGANAWA, SHINICHI KONDO, TOMIO TAKEUCHI
1992 Volume 45 Issue 12 Pages
1925-1929
Published: December 25, 1992
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A streptomyces metabolite, bellenamine, has been converted into D-β-lysinamide and cyclized bellenamine in an acidic solution at 75°C. The structure of the new cyclized compound was assigned as (
R)-6-(3-aminopropyl)-1, 3-diazacyclohexan-4-one by spectral analyses. [1-
13C,
Amide, 1'-
15N
2]bellenamine, which has been isolated from the culture by feeding both L-[1-
13C]lysine and [
15NH
4]
2SO
4 to a synthetic medium, was degraded under acidic condition to obtain the stable isotope labeled D-β-lysine, D-β-lysinamide and cyclized bellenamine. These labeled compounds were analyzed by
13C and
15N NMR spectra, and will be used for the biosynthetic study on bellenamine.
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YOSHIYUKI KOYAMA, SHYH-PYNG HUANG, DAISHIRO IKEDA, SHINICHI KONDO, TOM ...
1992 Volume 45 Issue 12 Pages
1930-1938
Published: December 25, 1992
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The 1, 3-dipolar cycloaddition of nitrile oxide with 3-vinylcephalosporin provided diastereomeric isomers of 3-(isoxazolin-5-yl)cephalosporin. Cycloaddition of nitrile oxide with 3-(dimethylaminovinyl)cephalosporin gave 3-(isoxazol-4-yl)cephalosporin. These semisynthetic cephalosporins with an aminothiazole in the C-7 side chain showed moderate antibacterial activities.
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SHYH-PYNG HUANG, YOSHIYUKI KOYAMA, DAISHIRO IKEDA, SHINICHI KONDO, TOM ...
1992 Volume 45 Issue 12 Pages
1939-1948
Published: December 25, 1992
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The syntheses and
in vitro antibacterial activities of 3-(isoxazolidin-5-yl)- and 3-(isoxazolidinium-5-yl)cephalosporins are described. 1, 3-Dipolar cycloaddition of 3-vinylcephalosporin with nitrone gave diastereomeric isomers of 3-(isoxazolidin-5-yl)cephalosporin. The antibacterial activities of 3'-(
S)-isomers were superior to those of 3'-(
R)-isomers. The quaternarization of isoxazolidine ring increased the antibacterial activity. Among them, compound
10b with a hydroxyimino group in the C-7 side chain showed potent activities against staphylococci and compound
10f with an
N-hydroxypyridone exhibited an excellent antipseudomonal activity.
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TUTOMU SATO, KOJI NAGAI, KENICHI SUZUKI, MOTO MORIOKA, TAKESHI SAITO, ...
1992 Volume 45 Issue 12 Pages
1949-1952
Published: December 25, 1992
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V. GLUTAMIC ACID- AND LEUCINE-DERIVED AMINO ACIDS IN PNEUMOCANDIN A0 (L-671, 329) AND DISTINCT ORIGINS OF THE SUBSTITUTED PROLINE RESIDUES IN PNEUMOCANDINS A0 AND B0
AKINLOLU A. ADEFARATI, OTTO D. HENSENS, E. TRACY TURNER JONES, JAN S. ...
1992 Volume 45 Issue 12 Pages
1953-1957
Published: December 25, 1992
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EISAKU TSUJII, NOBUHARU SHIGEMATSU, HIROSHI HATANAKA, MICHIO YAMASHITA ...
1992 Volume 45 Issue 12 Pages
1958-1960
Published: December 25, 1992
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MASAHIRO HATSU, HIROSHI NAGANAWA, TAKAAKI AOYAGI, TOMIO TAKEUCHI, YOSH ...
1992 Volume 45 Issue 12 Pages
1961-1962
Published: December 25, 1992
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TADAMICHI SONODA, KIMIKO KOBAYASHI, MAKOTO UBUKATA, HIROYUKI OSADA, KI ...
1992 Volume 45 Issue 12 Pages
1963-1965
Published: December 25, 1992
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YOSHIYUKI KOYAMA, SHYH-PYNG HUANG, DAISHIRO IKEDA, SHINICHI KONDO, TOM ...
1992 Volume 45 Issue 12 Pages
1966-1969
Published: December 25, 1992
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TAKANAO OTSUKA, SHIGEHIRO TAKASE, HIROSHI TERANO, MASAKUNI OKUHARA
1992 Volume 45 Issue 12 Pages
1970-1973
Published: December 25, 1992
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LI-JIANG XUAN, SAO-HUA XU, HAI-LAN ZHANG, YA-MING XU, MING-QING CHEN
1992 Volume 45 Issue 12 Pages
1974-1976
Published: December 25, 1992
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TOMOMI HIDAKA, MAKOTO HIDAKA, HARUO SETO
1992 Volume 45 Issue 12 Pages
1977-1980
Published: December 25, 1992
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RALPH H. LAMBALOT, DAVID E. CANE
1992 Volume 45 Issue 12 Pages
1981-1982
Published: December 25, 1992
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MAKOTO SUNAGAWA, HARUKI MATSUMURA, MASATOMO FUKASAWA
1992 Volume 45 Issue 12 Pages
1983-1985
Published: December 25, 1992
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