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I. PRODUCING ORGANISM, FERMENTATION, ISOLATION AND BIOLOGICAL ACTIVITY
E. K. WEIBEL, P. HADVARY, E. HOCHULI, E. KUPFER, H. LENGSFELD
1987 Volume 40 Issue 8 Pages
1081-1085
Published: August 25, 1987
Released on J-STAGE: April 19, 2006
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Lipstatin, a new and very potent inhibitor of pancreatic lipase (the key enzyme of intestinal fat digestion) was isolated from
Streptomyces toxytricini. Lipstatin contains a β-lactone structure that probably accounts for the irreversible lipase inhibition. The IC
50 of lipstatin for pancreatic lipase is 0.14 μM. In mice triolein absorption was dose-dependently inhibited by lipstatin, whereas oleic acid was absorbed normally. Other pancreatic enzymes, such as phospholipase A2 and trypsin, were not inhibited even at an inhibitor concentration of 200 μM.
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II. CHEMISTRY AND STRUCTURE ELUCIDATION
E. HOCHULI, E. KUPFER, R. MAURER, W. MEISTER, Y. MERCADAL, K. SCHMIDT
1987 Volume 40 Issue 8 Pages
1086-1091
Published: August 25, 1987
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The structure of a new pancreatic lipase inhibitor, lipstatin, produced by
Streptomyces toxytricini was determined as (2
S, 3
S, 5
S, 7
Z, 10
Z)-5-[(
S)-2-formamido-4-methylpentanoyloxy]2-hexyl-3-hydroxy-7, 10-hexadecadienoic lactone by spectroscopic and chemical methods. Structurally lipstatin is closely related to the known esterase inhibitor esterastin. It contains a
N-formyl-L-leucine side chain instead of the
N-acetyl-L-asparagine in esterastin.
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YUZURU MATSUDA, Kozo ASANO, ISAO KAWAMOTO, HIROSHI KASE
1987 Volume 40 Issue 8 Pages
1092-1100
Published: August 25, 1987
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K-259-2, a new inhibitor of Ca
2+ and calmodulin-dependent cyclic nucleotide phosphodiesterase, was isolated from the cultured broth of
Micromonospora olivasterospora K-259. K-259-2 has an anthraquinone moiety in its structure. IC
50 values for the effect of K-259-2 against Ca
2+ and calmodulin-stimulated activity of the enzyme preparations from bovine brain and heart were 6.6 and 2.9μM, respectively. On the other hand, basal activity (the activity in the presence of ethylene bis(oxyethylenenitrilo)tetraacetic acid (EGTA) instead of Ca
2+/calmodulin) of the bovine brain enzyme, calmodulin-independent cyclic nucleotide phosphodiesterase from bovine heart, and protein kinase C from rat brain were inhibited by K-259-2 to a lesser extent with IC
50 values of 27.4, 40.7 and 45.8 μM, respectively.
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TOHRU YASUZAWA, MAYUMI YOSHIDA, KUNIKATSU SHIRAHATA, HIROSHI SANO
1987 Volume 40 Issue 8 Pages
1101-1103
Published: August 25, 1987
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The structure of K-259-2, a potent inhibitor of Ca
2+ and calrnodulin-dependent cyclic nucleotide phosphodiesterase, was determined to be 3-(2
Z-2-ethyl-2-butenyl)-l, 6, 8-trihydroxyanthraquinone-2-carboxylic acid by chemical conversion and spectral studies.
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YUZURU MATSUDA, HIROSHI KASE
1987 Volume 40 Issue 8 Pages
1104-1110
Published: August 25, 1987
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KS-619-1, a new inhibitor of Ca
2+ and calmodulin-dependent cyclic nucleotide phosphodiesterase, was isolated from the cultured broth of
Streptomyces californicus. KS-619-1 has an anthraquinone moiety. IC
50 values for the effect of KS-619-1 on Ca
2+ and calmodulin-stimulated activity of bovine brain and heart enzymes were 2.0 and 1.5 μM, respectively. On the other hand, basal activity (the activity in the presence of ethylene bis(oxyethylenenitrilo)-tetraacetic acid (EOTA) instead of Ca
2+/calmodulin) of the bovine brain enzyme, calmodulin-independent cyclic nucleotide phosphodiesterase from bovine heart, and protein kinase C from rat brain were inhibited by KS-619-1 to a lesser extent with IC
50 values; 12.3, 25.9 and 151 μM, respectively.
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TOHRU YASUZAWA, MAYUMI YOSHIDA, KUNIKATSU SHIRAHATA, HIROSHI SANO
1987 Volume 40 Issue 8 Pages
1111-1114
Published: August 25, 1987
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The structure of KS-619-1, a potent inhibitor of Ca
2+ and calmodulin-dependent cyclic nucleotide phosphodiesterase, was determined to be 8, 13-dioxo-3-(2-oxopropyl)-5, 6, 8, 13-tetrahydro-l, 7, 9, 11-tetrahydroxybenz[a]naphtacene-2-carboxylicacid by spectral studies of KS-619-1 and its methyl derivative.
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I. 2-NORERYTHROMYCINS, ISOLATION AND STRUCTURAL DETERMINATIONS
JAMES B. MCALPINE, JAMES S. TUAN, DAVID P. BROWN, KEVIN D. GREENER, DA ...
1987 Volume 40 Issue 8 Pages
1115-1122
Published: August 25, 1987
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Novel macrolide antibiotics have been isolated from a genetically manipulated actinomycete. The major components produced have been isolated and identified as 2-norerythromycins A, B, C and D by mass spectrometry and extensive ID and 2D NMR experiments.
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KOHKI KIYOSHIMA, KAZUAKI TAKADA, MASAO YAMAMOTO, KATSURO KUBO, ROKURO ...
1987 Volume 40 Issue 8 Pages
1123-1130
Published: August 25, 1987
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2'''-Demethoxytylosin (component
IIIc), 2'''-demethoxy-4'''-
epi-tylosin (component
IIId) and 2'''-
O-demethyltylosin (component
Vb) were produced by blocked mutant strains of
Streptomyces fradiae. Fermentation, isolation, structure determination and biosynthetic considerations of these tylosin analogs are described.
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ITSUO KUROBANE, PHYLLIS L. DALE, LEO C. VINING
1987 Volume 40 Issue 8 Pages
1131-1139
Published: August 25, 1987
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Cultures of
Streptomyces griseus grown under phosphate-limiting conditions produced a complex of green products. Three of these were separated from the mixture and characterized. One was identified as viridomycin A, the ferrous chelate of 4-hydroxy-3-nitrosobenzaldehyde; the second (actinoviridin A) was the corresponding carboxylic acid chelate and the third (viridomycin E) was a hybrid chelate containing both the aldehyde and acid ligands. Only two out of nine strains of
S. griseus examined produced viridomycins and the ligands were biosynthesized only in media from which phosphate had been exhausted. Optimization of the production medium showed that fructose and alanine were the most favorable carbon and nitrogen sources and that relatively high concentrations of ferrous ions were necessary. The results suggest that viridomycins are not produced by
S. griseus as iron scavengers in response to iron deficiency but as secondary metabolites that are stabilized adventitiously in the broth by metal ion chelation.
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II. CHEMICAL STRUCTURES
TOSHIHIKO ANDO, SHIGEYOSHI MIYASHIRO, KAZUO HIRAYAMA, TAKAO KIDA, HIRO ...
1987 Volume 40 Issue 8 Pages
1140-1145
Published: August 25, 1987
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The new, belonging to the streptothricin-group antibiotics AN-201 I, II and III were found to be produced by a soil actinomycete identified as
Streptomyces nojiriensis C-13. The chemical structures and the physical and spectroscopic properties of these compounds are reported here. On the basis of NMR and fast atom bombardment mass spectrometry (FAB-MS) spectra the antibiotics were identified as N
β-acetylated derivatives of streptothricins E, D and F.
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PETER TRAXLER, WERNER TOSCH, OTO ZAK
1987 Volume 40 Issue 8 Pages
1146-1164
Published: August 25, 1987
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A series of papulacandin B derivatives was synthesized and their
in vitro and
in vivo activity against
Candida albicans and other fungi was established. The biological data have shown that some 10-alkyl ether and 11-acylamino derivatives exhibit an improved
in vivo activity compared to papulacandin B whereas derivatization in other positions of the molecule led to less potent compounds.
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TETSUSHI SAINO, KENJI SEYA, RINZO NISHIZAWA, TOMOHISA TAKITA, TAKAAKI ...
1987 Volume 40 Issue 8 Pages
1165-1169
Published: August 25, 1987
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p-Hy droxyubenimex, (2
S, 3
R)-3 -amino-2-hy droxy -4-
p-hy droxyphenylbutyryl-L-leucine, was synthesized starting from D-tyrosine. The structure and stereochemistry of the synthesized product were confirmed by comparison with p-hydroxyubenimex that was chemically transformed from ubenimex, an aminopeptidase inhibitor of microbial origin. Compared to ubenimex,
p-hydroxyubenimex is more active against aminopeptidase B but less active against leucine aminopeptidase. By using the synthetic
p-hydroxyubenimex as a reference sample, one of the metabolites of ubenimex was identified as
p-hydroxyubenimex. The (2
R, 3
R)-stereoisomer of
p-hydroxyubenimex was also prepared. However, its activity against arninopeptidases was much weaker.
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MARIO GONZALEZ DE LA PARRA, C. RICHARD HUTCHINSON
1987 Volume 40 Issue 8 Pages
1170-1174
Published: August 25, 1987
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Brefeldin C (
2) is the penultimate intermediate in the biosynthetic pathway to brefeldin A (
1). Using stereospecifically
2H-labeled forms of
2, the hydroxylation of
2 to
1 is shown to involve stereospecific remova1 of the 7
pro-S hydrogen from
2.
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Kozo TOMATSU, SHIGEYUKI ANDO, SHINJI MASUYOSHI, SHOICHIRO KONDO, MINOR ...
1987 Volume 40 Issue 8 Pages
1175-1183
Published: August 25, 1987
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A new semisynthetic oral cephalosporin, BMY-28100, was evaluated for
in vitro and
in vivo antibacterial activities in comparison with cefaclor and cephalexin. BMY-28100 showed
in vitro activity 3- and 10-fold more potent than that of cefaclor against
Staphylococcus aureus and
Streptococcus pneumoniae, respectively. BMY-28100 was slightly better than cefaclor and about 4 times more active than cephalexin against
Haemophilus influenzae and
Neisseria gonorrhoeae.
Escherichia coli,
Klebsiella pneumoniae and
Proteus mirabilis were comparably susceptible to BMY-28100 and cefaclor. The bactericidal activity of BMY-28100 against
S. aureus,
E. coll and
P. mirabilis was equal to or twice as high as MIC value, which was similar to that of cefaclor. The stability of BMY-28100 against penicillinases was nearly comparable to that of cefaclor, whereas cefaclor was somewhat unstable to cephalosporinases. BMY-28100 was about twice as active as cefaclor against three Gram-positive bacterial infections. BMY-28100 was also more potent against infections of
H. influenzae and
P. mirabilis, but slightly less active against
E. coli Juhl than cefaclor. Blood level parameters of BMY-28100 were significantly superior to those of cefaclor and slightly better than cephalexin in mice and rats. The urinary recovery of BMY-28100 was somewhat higher and comparable to that of cefaclor and cephalexin, respectively. BMY-28100 was more stable than cefaclor in human and calf sera at 37°C.
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II. EVALUATION OF THE PHARMACOKINETIC BEHAVIOR AND THE CHEMOTHERAPEUTIC ACTIVITY IN ANIMALS
N. KLESEL, D. ISERT, M. LIMBERT, G. SEIBERT, E. SCHRINNER, C. JOHNSON
1987 Volume 40 Issue 8 Pages
1184-1192
Published: August 25, 1987
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The pharmacokinetic and chemotherapeutic properties of the new penem antibiotic HRE 664 (Fig. 1) were evaluated in experimental animals. High and sustained blood and serum levels were achieved following parenteral injection in mice, rats, dogs and monkeys. Half-lives ranged from 27 to 40 minutes in the various species tested. The antibiotic was well distributed in the rodents and penetrated well into tissues and body fluids. At 30 minutes after subcutaneous administration to mice (50 mg/kg), concentrations of between 12.4 and 35.9 μg/g were measured in the lungs, liver, heart and kidneys, that is 33-95% of the corresponding level in murine blood (37.7 μg/ml).
In experimentally induced infections in mice, HRE 664 displayed good chemotherapeutic activity particularly against septicemias caused by methicillin-sensitive and methicillinresistant
Staphylococcus aureus strains and on abscess formation induced by
Bacteroides fragilis. Most of the cephalosporins and other β-lactam antibiotics exhibited low efficacy against these strains of bacteria.
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KYUICHI NEMOTO, FUMINORI ABE, TOMOHISA TAKITA, TERUYA NAKAMURA, TOMIO ...
1987 Volume 40 Issue 8 Pages
1193-1194
Published: August 25, 1987
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KUNIO ISSHIKI, YOSHIKAZU TAKAHASHI, MAYUMI OKADA, TSUTOMU SAWA, MASA H ...
1987 Volume 40 Issue 8 Pages
1195-1198
Published: August 25, 1987
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KUNIO ISSHIKI, YOSHIKAZU TAKAHASHI, TSUTOMU SAWA, HIROSHI NAGANAWA, TO ...
1987 Volume 40 Issue 8 Pages
1199-1201
Published: August 25, 1987
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KUNIO ISSHIKI, YOSHIKAZU TAKAHASHI, TSUTOMU SAWA, HIROSHI NAGANAWA, TO ...
1987 Volume 40 Issue 8 Pages
1202-1203
Published: August 25, 1987
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PIOTR BOROWICZ
1987 Volume 40 Issue 8 Pages
1204-1206
Published: August 25, 1987
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KUNIO ISSHIKI, MASAYA IMOTO, TOMIO TAKEUCHI, HAMAO UMEZAWA, TOSHIO TSU ...
1987 Volume 40 Issue 8 Pages
1207-1208
Published: August 25, 1987
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KUNIO ISSHIKI, MASAYA IMOTO, TSUTOMU SAWA, KAZUO UMEZAWA, TOMIO TAKEUC ...
1987 Volume 40 Issue 8 Pages
1209-1210
Published: August 25, 1987
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EUGENE L. DULANEY, CAROL A. JACOBSEN
1987 Volume 40 Issue 8 Pages
1211-1212
Published: August 25, 1987
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