The Journal of Antibiotics

S14-95, a Novel Inhibitor of the JAK/STAT Pathway from a Penicillium species

GERHARD ERKEL, JAN RETHER, TIMM ANKE, OLOV STERNER

2003 Volume 56 Issue 4 Pages 337-343
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.337

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In a search for new inhibitors of the IFN-γ mediated signal transduction in HeLa S3 cells using secreted alkaline phosphatase (SEAP) as reporter gene, a novel compound, designated as S14-95 was isolated from fermentations of the imperfect fungus Penicillium sp. 14-95. The compound inhibits the IFN-γ mediated expression of the reporter gene with IC₅₀ values of 2.5-5μg/ml (5.4-10.8μM). Furthermore the compound inhibited the expression of the proinflammatory enzymes COX-2 and NOS II at 5μg/ml (10.8μM) in LPS/IFN-γ stimulated J774 mouse macrophages. Studies on the mode of action of the compound revealed that the inhibition of the IFN-γ dependent signaling pathway is caused by an inhibition of the phosphorylation of the STAT 1α transcription factor. In addition, S14-95 inhibited the activation of the p38 MAP kinase, which is involved in the inducible expression of many proinflammatory genes.

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Terreulactones A, B, C, and D: Novel Acetylcholinesterase Inhibitors Produced by Aspergillus terreus

I. Taxonomy, Fermentation, Isolation and Biological Activities

KYUNG-MI CHO, WON-GON KIM, CHONG-KIL LEE, ICK-DONG YOO

2003 Volume 56 Issue 4 Pages 344-350
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.344

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In the course of screening for selective inhibitors of acetylcholinesterase from the microbial metabolites, four new meroterpenoid compounds, terreulactones A, B, C and D were isolated from solid state fermentation of Aspergillus terreus Fb000501. They showed potent inhibitory activities against acetylcholinesterase with IC₅₀ values in range of 0.06-0.42μM. In addition, they exhibited more than 500-3000 times selectivity for acetylcholinesterase compared with butyrylcholinesterase.

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Terreulactones A, B, C, and D: Novel Acetylcholinesterase Inhibitors Produced by Aspergillus terreus

II. Physico-chemical Properties and Structure Determination

WON-GON KIM, KYUNG-MI CHO, CHONG-KIL LEE, ICK-DONG YOO

2003 Volume 56 Issue 4 Pages 351-357
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.351

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Terreulactones A, B, C, and D, new meroterpenoid compounds with potent anti-acetylcholinesterase activity, were determined to be mixed polyketides-terpenoid structures by spectroscopic studies.

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YM-254890, a Novel Platelet Aggregation Inhibitor Produced by Chromobacterium sp. QS3666

MASATOSHI TANIGUCHI, KOJI NAGAI, NAKAKO ARAO, TOMIHISA KAWASAKI, TETSU ...

2003 Volume 56 Issue 4 Pages 358-363
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.358

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A novel platelet aggregation inhibitor, YM-254890, was isolated from the culture broth of strain QS3666. This strain was isolated from a soil sample collected at Okutama, Tokyo, Japan, and was identified as Chromobacterium sp. by morphological and physiological criteria. YM-254890 was purified from the culture supernatant by solvent extraction, ODS and silica gel flash chromatography, followed by preparative HPLC. YM-254890 inhibited ADP-induced platelet aggregation in human platelet-rich plasma with an IC₅₀ value below 0.6μM by blocking the P2Y₁ receptor-signal transduction pathway.

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Ripromycin and Other Polycyclic Macrolactams from Streptomyces sp. Tü 6239

Taxonomy, Fermentation, Isolation and Biological Properties

MARCELO BERTASSO, MEIKE HOLZENKÄMPFER, AXEL ZEECK, ERKO STACKEBRA ...

2003 Volume 56 Issue 4 Pages 364-371
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.364

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Strain Tü 6239 was isolated from a soil sample collected in Brazil and determined as a new species of the genus Streptomyces. In the course of our HPLC-diode array screening program three metabolites were detected in the culture filtrate and mycelium extracts of strain Tü 6239. They were characterised as members of the macrolactam group, the new compound ripromycin (1), the previously described ikarugamycin (2) and a new derivative of it, ikarugamycin epoxide (3). They show antibiotic activities against Gram-positive bacteria and cytostatic effects to various human tumor cell lines.

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Biosynthetic Studies on a Myxobacterial Antibiotic, Cystothiazole A

Biosynthetic Precursors of the Carbon Skeleton

YOSHIHIRO SUZUKI, YOUJI SAKAGAMI, MAKOTO OJIKA

2003 Volume 56 Issue 4 Pages 372-378
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.372

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Biosynthetic studies on cystothiazole A (1), a β-methoxyacrylate-type antifungal compound from a myxobacterium, were performed by feeding the producing organism, Cystobacter fuscus, with stable-isotope-labeled compounds including [2-¹³C]acetate, [1, 2-¹³C₂]acetate, [1-¹³C]propionate, L-[1-¹³C]serine, L-[methyl-¹³C]methionine, and DL-valine-d₈. The polyketide moiety of 1 was found to be derived from acetate and propionate, the bithiazole moiety from L-serine, the O-methyl groups from the S-methyl group of L-methionine, and the isopropyl moiety from L-valine, which should be the metabolic precursor of isobutyryl-CoA.

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An Innovative Classification of, and a New Structure-activity-relationship Approach to Degradation Kinetics of Cephalosporins

An Attempt to Enhance the Therapeutic Activity

EIICHI AKAHO, HITOMI NAKAYAMA

2003 Volume 56 Issue 4 Pages 379-391
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.379

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Degradation kinetics of cephalosporins was innovatively classified into six groups according to its mechanism that is based on the attached functional and/or substituent groups. 3-Position plays an important role in the degradation kinetics, and they are classified into three major groups; one with a 3-acetoxy group, another with a 3-deacetoxy group, and the other without a 3-acetoxy group. Each group is further subdivided depending on whether it contains 7-x-amino group or not. The order of the alkaline hydrolysis of cephalosporins coincided with the order of the degree of their antibacterial activities. This provides an evidence to support the hypothesis that the biological activity of β-lactam antibiotics depends upon the reactivity of the β-lactam moiety. At the same time, the compound should be stable, and the stability is often related to the reactivity of 3-position. Combination products of biodegradable cephalosporins and acid-stable cephalosporins are desired products. An example of such products produced by chemical modifications stated above will be the one with a good leaving group at the 3-position that is not hydrolyzed.

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Novel 12-Membered Ring Macrolides with Activity against Erythromycin-resistant Organisms

PETER A. NEMOTO, XIAOLIN ZHANG, STEVAN DJURIC, ZHENKUN MA

2003 Volume 56 Issue 4 Pages 392-398
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.392

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A series of novel 12-membered ring macrolides was designed based on available information on structure-activity relationships and macrolide-ribosome interactions. Compounds with the desosamine and the anchor group properly attached to the 12-membered lactone ring exhibited improved activity against erythromycin-resistant organisms.

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Synthesis and Biological Evaluation of Novel Leucomycin Analogues Modified at the C-3 Position

I. Epimerization and Methylation of the 3-Hydroxyl Group

TAKESHI FURUUCHI, KEN-ICHI KURIHARA, TAKUJI YOSHIDA, KEIICHI AJITO

2003 Volume 56 Issue 4 Pages 399-414
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.399

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The synthesis and biological evaluation of sixteen-membered macrolides modified at the C-3 position are described. 3-Epi-leucomycin A₇ (9), 3-O-acyl-3-epi-leucomycin A₇ analogues (11a-11e), 3-O-acylleucomycin A₇ analogues (13b-13e) and 3-O-methylleucomycin analogues (16a, 16b and 22) were synthesized via fully protected intermediates (7, 5a, 5b and 20). After appropriate modification, subsequent deprotections were performed to furnish a variety of leucomycin analogues. Methylation of the 3-hydroxyl group was found to improve the pharmacoprofile of leucomycin antibiotics. 3-O-Methylrokitamycin (16b) showed enhanced antibacterial activity in vitro and 3, 3"-di-O-methyl-4"-O-(3-methylbutyl)leucomycin V (22) exhibited improved metabolic stability in rat plasma in vitro.

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A New Macrolide Antibiotic with Antitumor Activity Produced by Streptomyces sp. CS, a Commensal Microbe of Maytenus hookeri

CHUNHUA LU, YUEMAO SHEN

2003 Volume 56 Issue 4 Pages 415-418
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.415

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A New Antifungal Sterol Sulfate, Sch 601324, from Chrysosporium sp.

SHU-WEI YANG, ALEXEI BUEVICH, TZE-MING CHAN, JOSEPH TERRACCIANO, GUODO ...

2003 Volume 56 Issue 4 Pages 419-422
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.419

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Colony PCR Amplification of Actinomycete DNA

ESTHER W. N. GATHOGO, ALASTAIR C. W. WAUGH, NATAŠA PERIC, MARIA ...

2003 Volume 56 Issue 4 Pages 423-424
Published: April 25, 2003
Released on J-STAGE: January 27, 2009

DOIhttps://doi.org/10.7164/antibiotics.56.423

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