Abstract A new glutarimide antibiotic epiderstatin was synthesized in dl-form. Horner-Wadsworth-Emmons reaction of an aldehyde with a phosphonate gave enones which were converted into (±)-epiderstatin and its diastereomer via intramolecular amidoselenation as a key step.

Isolation Actiketal was produced by S. pulveraceus subsp. epiderstagenes which is a producing strain of epiderstatin and its fermentation was carried out as described previously.1} All the purification steps were monitored by measuring the inhibitory activity of incorporation of [3H]thymidine into quiescent Balb/MK cells stimulated by EGF.1} Culture broth (72 liters) was filtered with the aid of Celite. The filtrate (55 liters) was extracted with the samevolumeof ethyl acetate. The organic layer dried over anhydroussodiumsulfate was evaporated under reduced pressure. The oily extract (21.8 g) was applied to a silica gel column (76 i.d. x 430mm) and eluted with chloroform methanol (92 : 8). The eluate was fractionated into each 300ml of volume and the active fractions were combined and evaporated. The resulting oily material (1 3. 1 g) was rechromatographed on a silica gel column (45 i.d. x 700mm) with chloroform-methanol (95 : 5). The eluate was fractionated into each 23ml of volume, and the active fractions were combined and evaporated. The resulting oily material (4.57 g) was dissolved in a small volume of methanol and was applied to gel filtration through a Sephadex LH-20 column equilibrated with 80%methanol.The eluate was fractionated into each 10ml of volume and the active fractions were combined and evaporated. From the dried material (1 8.0 mg), actiketal (4.5 mg) was purified by the preparative HPLC using a reverse phase column (Senshu Pak ODS-5251-N, 20 i.d. x 250mm, monitored by UVat 220nm) with 50% methanol as a solvent.

This study was carried out to elucidate the mode of bacteriostatic property of xanthostatin (XS), a novel depsipeptide antibiotic with an N-acetylglycine side chain and selective antimicrobial activity against Xanthomonas spp. Two biotransformed XSs were isolated by the treatment of XS with the cell lysate of Xanthomonas campestris pv. citri, a solvent partition, preparative TLC, and HPLC. Structure determination of those two biotransformed XSs demonstrated deletion of the N-acetylglycine side chain. Noteworthily, they showed no antimicrobial activity against Xanthomonas spp. This result suggests that the N-acetylglycine side chain plays a critical role in the antimicrobial activity of XS, and that the bacteriostatic property of XS is due to susceptibility of the ester bond between the hexadepsipeptide nucleus and the N-acetylglycine side chain to hydrolytic enzyme(s) produced by Xanthomonas spp.

Liposidomycins are atypical lipid-bearing nucleoside antibiotics that inhibit bacterial peptidoglycan synthesis. A producing strain was identified as a Streptomyces sp. from its cultural characteristics and physiological properties. It produced new types of liposidomycins that lacked sulfate and/or 3-methylglutaric acid moieties present in known liposidomycins by changing medium components. Liposidomycins which have no sulfate moiety, exhibited more potent antimicrobial activity. Thus liposidomycins are the unique antibiotics showing highly specific inhibition toward bacterial peptidoglycan synthesis and could be a useful clinical antibiotic agent.

Cette invention se rapporte a des antibiotiques RK-1061 ayant une nouvelle structure chimique et a un procede pour leur preparation. Ces antibiotiques ont une formule structurale representee par la formule generale suivante (I), ou A represente R1 ou R1CH(OR2)CH2, R2 represente un reste d'acide 3-methylglutarique et R3 represente un groupe sulfate ou un atome d'hydrogene. Le procede de cette invention consiste a cultiver un champignon Actinomyces appartenant au genre Streptomyces et a isoler l'antibiotique RK-1061 de cette culture. Les Streptomyces de l'espece SN-1061M (FERM BP-5800) sont capables de produire de facon stable l'antibiotique RK-1061 avec une productivite elevee.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Tautomycin, a well-known protein phosphatase inhibitor, exists in two forms (acid anhydride and diacid). We successfully isolated them and proved that relationship of tautomycin and its conformational analysis are also described.

tion of the sample at pH 1 for 20 minutes in a boilingwater bath. This result was constantly observed in every tests repeated for the confirmation. Thus, the following separation procedure was monitored by the inhibitory activity observed after the treatment of the sample in the same manner. This research procedure resulted in the isolation of a proto-inhibitor (2) as described bellow. Spores of the producing strain was inoculated into each of two 500-ml Erlenmeyer flasks containing 70ml of a mediumconsisting of glucose 3%, soluble starch 2%, soybean meal 2%, K2HPO40.5% and MgSO47H2O 0.05% (pH 6.5) and cultured at 28°C for 48 hours on a rotary shaker at 300rpm. The seed culture (3.5ml) was then inoculated in each of thirty eight 500-ml Erlenmeyer flasks containing 70 ml of the same medium and cultured for 84 hours under the same condition. The isolation procedure for 2 is outlined in Fig. 2. The

Three novel 36-membered macrolide antibiotics, RS-22A, B and C produced by Streptomyces violaceusniger have been isolated. These antibiotics were purified from an acetone extract of the mycelia followed by butanol extraction, centrifugal partition chromatography and HPLC. RS-22A, B, C showed antimicrobial activity against fungi and Gram-positive bacteria.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Three novel 36-membered macrolide antibiotics, RS-22A, B and C produced by Streptomyces These antibiotics were purified from an acetone extract of the mycelia followed by butanol extraction, centrifugal partition chromatography and HPLC. RS-22A, B, C showed antimicrobial activity against fungi and Gram-positive bacteria.

This chapter reviews polyoxins and related nucleosides. The polyoxins, nikkomycins, blasticidin S, and mildiomycin have highly modified bases, sugars and amino acids, and they have complex biosynthetic pathways; the sequence of reactions proposed for polyoxin formation would require more than a dozen enzymes. Introduction of a one-carbon unit into the 5-position of pyrimidines in polyoxins and mildiomycin is catalyzed by an enzyme system different from the thymidylate synthetase used for the DNA precursor. The main structural difference in the substrate is that the 2′-hydroxyl is present. Control of antibiotic biosynthesis by targeted inhibitors produces specific components of the polyoxin group. With polyoxins and mildiomycin, adding 5-halogenopyrimidines yielded 5-halogeno analogs. The 5-fluoropolyoxins so produced can be isolated and are chemically and biologically characterized. Pyrimidine auxotrophic mutants are isolated by NTG treatment of S. tendae; they produce exclusively nikkomycin X that has formylimidazolinone as the base. Mutasynthesis using the pyr mutants yields 5-methyl and 5-hydroxymethyluracil analogs.

Tautomycin isolated fromStreptomyces spiroverticillatus is an inhibitor of protein phosphatases 1 and 2A. Tautomycin induced hyperphosphorylation of cytokeratin peptides in human keratinocytes (PHK 16-I cells) 30 times less strongly than did okadaic acid. Repeated applications of tautomycin (30 μg, 40 nmol/application) did not induce tumor promotion in a two-stage carcinogenesis experiment on mouse skin initiated with 7,12-dimethylbenz[a]anthracene, whereas okadaic acid (1 μg, 1.2 nmol/application) as a control induced tumor promotion strongly. As for mucosa or rat glandular stomach, tautomycin induced ornithine decarboxylase 4 h after intubation into the stomach. The tumor-promoting activity of tautomycin was next studied in the glandular stomach initiated withN-methyl-N′-nitro-N-nitrosoguanidine (MNNG). Administration of tautomycin in the diet (1 mg rat−1 day−1), from week 9 to week 52 of the experiment, inhibited rather than enhanced tumor development in the glandular stomach initiated with MNNG. The percentages of tumor-bearing rats of the groups treated with MNNG plus tautomycin, MNNG alone, and tautomycin alone were 20.0%, 40.6%, and 0% respectively in week 52. The reason for the absence of tumor-promoting activity of tautomycin was studied in relation to tumor necrosis factor α (TNFα), an endogenous tumor promoter. We found that tautomycin neither enhanced TNFα mRNA expression in mouse skin nor induced TNFα release in a human stomach cancer cell line (KATO III cells), whereas okadaic acid did both. These results indicate that not all inhibitors of protein phosphatases are tumor promoters, and suggest that tumor promotion of the okadaic acid class of compounds is mediated by TNFα.

The absolute configuration of reveromycin A, a new inhibitor of the signal transduction of epidermal growth factor (EGF), is determined on the basis of chemical degradation and spectroscopic evidence.

An efficient six-step degradation method for the protein phosphatase inhibitor, tautomycin (1), was developed in order to synthesize various analogues of 1 for their biological evaluation. This route allows rapid and multi-gram access to key intermediate 2 in the total synthesis of 1.

The absolute configurations of all the chiral centres of tautomycin, a new protein phosphatase inhibitor from Streptomyces spiroverticillatus, have been determined. Because of its non-crystallinity and flexibility, the absolute configurations of tautomycin, which possesses 13 chiral centres were determined on the basis of chemical degradation and spectroscopic evidence, with aid from conformational calculations.