Stachybocins A, B and C, novel endothelih (ET) receptor antagonists, were isolated from the culture filtrate of Stachybotrys sp. M6222. They were extracted with ethyl acetate and then purified by alumina and silica gel column chromatographies. The molecular formulae of Stachybocins were determined to be C₅₂H₇₀N₂O₁₀ (stachybocin A) and C₅₂H₇₀N₂O₁₁ (stachybocins B and C). It was supposed that they consisted of spirobenzofuran and terpene units from NMR spectra. They showed the inhibitory activity of ¹²⁵I-ET-1 binding to rat ET_A, human ET_A and human ET_B receptors.

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The structures of Stachybocins A, B and C, new endothelin receptor antagonists, were determined by NMR spectral analysis using pulse-field-gradient techniques. Stachybocin A consists of two spirobenzofuran units each fused to a substituted decalin, which were connected by a lysine residue. Stachybocins B and C are derivatives of Stachybocin A with an additional hydroxy group at the same position in the different decalin unit.

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RES-1214-1 and -2, novel and non-peptidic endothelin antagonists, were isolated from the culture broth of a fungus, Pestalotiopsis sp. RE-1214. RES-1214-1 and -2 selectively inhibited the ET-1 binding to endothelin type A receptor (ET_A receptor) with IC₅₀ values of 1.5μM and 20μM, respectively. RES-1214-1 and -2 inhibited the increase in intracellular Ca²⁺ concentration elicited by 1 nM ET-1 in A10 cells. Taxonomy of producing strains, fermentation, isolation, structural determination, and biochemical properties of RES-1214-1 and -2 are described.

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A new platelet aggregation inhibitor, bassiatin, was isolated from the cultured broth of Beauveria bassiana which had been isolated from a soil sample collected in Yunnan province, China. The structure of bassiatin was determined to be (3S, 6R)-4-methyl-6-(1-methylethyl)-3-phenylmethyl-1, 4-perhydrooxazine-2, 5-dione by NMR analysis, X-ray crystallographic analysis and chemical synthesis. Bassiatin inhibited ADP-induced aggregation of rabbit platelets with the IC₅₀ being 1.9×10^-4M.

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A new radical scavenger, named phenopyrrozin, was isolated from the culture broth of Penidllium sp. FO-2047. Phenopyrrozin was purified from whole broth by solvent extraction, silica gel chromatography, and HPLC. The structure of phenopyrrozin was elucidated as 5, 6, 7, 7a-tetrahydro2-hydroxy-l-phenyl-3H-pyrrolizin-3-one. The IC₅₀ of phenopyrrozin against lipid peroxidation induced by Cr₂K₂O₇ was 73μg/ml. Phenopyrrozin also reduced chromosomal aberrations induced by paraquat.

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A complex of metabolites consisting of two isomeric cyclic acylpeptides was isolated from a culture of Bacillus sp. A1238 by successive chromatographies on Amberlite XAD-7, silica gel and silica ODS columns. By a combination of spectroscopic and chemical analyses, the two subcomponents were identified as isomers of halobacillin, and the complex was designated isohalobacillin. Each molecule of isohalobacillin subcomponents contains either a 3-hydroxy-l-oxo-13-methyltetradecyl or a 3-hydroxy-1-oxo-12-methyltetradecyl moiety in place of a 3-hydroxy-loxopentadecyl moiety that is found in the halobacillin molecule. In a cell-free assay, isohalobacillin inhibited acyl-CoA: cholesterol acyltransferase by 50% at a concentration of 50μM. When added to a culture of macrophage J774, the agent inhibited oxidized low density lipoprotein-induced synthesis of cholesteryl ester from [¹⁴C]oleate without affecting surface binding, internalization and degradation of the lipoprotein in the cells.

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In the course of our screening for elastase inhibitors from microorganism, we have found two new cyclic-depsipeptides designated YM-47141 and 47142. In this paper, we describe the taxonomy of the producing organism and isolation, physico-chemical properties, and biological activities of YM-47141 and 47142.

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YM-47141 and YM-47142 are new elastase inhibitor produced by Flexibacter sp. Q17897. These structures were elucidated by MS and NMR spectral analysis. YM-47141 and YM-47142 were the cyclic pep tides containing tricarbonyl moiety hydrated on the center carbonyl carbon in DMSO-d₆.

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Potent anti-adherent activity was detected in fermentation extracts of microbial strain FO-5050. Active compounds designated macrosphelide A and B were isolated and the structure was determined to be 16-membered macrolide antibiotics possessing three ester bonds in the ring structure. Macrosphelide A dose-dependently inhibited the adhesion of HL-60 cells to LPS-activated HUVEC monolayer (IC₅₀, 3.5μM); macrosphelide B also inhibited HL-60 adhesion but to a lesser extent (IC₅₀, 36μM). Macrosphelide A did not show any antimicrobial and cytocidal activities at the concentration of 1000μg/ml and 100μg/ml, respectively.

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Sch 52900 (1) and Sch 52901 (2), two new inhibitors of c-fos proto-oncogene induction, have been isolated from the fermentation broth of the fungal culture (SCF-1168), Gliocladium sp. Along with compounds 1 and 2, a known compound verticillin A (3) was also obtained from the culture. Structure elucidation of 1 and 2, accomplished by analysis of spectral data in comparison with the data of 3, revealed both 1 and 2 were found to be closely related to the verticillin family of diketopiperazines. All three compounds prevented serum-stimulated transcription of the human c-fos promoter, using a fos/lac Z reporter gene assay, with IC₅₀ values of 1.5, 18 and 0.5μM for 1, 2 and 3, respectively. Northern analysis revealed that exposure of cells to compound 3 causes inhibition of both phorbol ester-induced c-fos induction and serum-induced JE induction in the absence of inhibiting RNA synthesis, as measured by [³H]uridine incorporation. These results suggest that this class of compounds exerts antitumor activity by blocking a signal transduction pathway that is common to and necessary for the induction of at least a subset of immediate early genes involved in cell proliferation.

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The new cytotoxic agents rakicidins A and B were isolated from cultured broth of a Micromonospora sp. Spectroscopic and amino acid analysis has shown that rakicidin A is a new cyclic lipopeptide, consisting of 4-amino-penta-2, 4-dienoic acid, 3-hydroxy-2, 4, 16-trimethylheptadecanoic acid, sarcosine, and 3-hydroxyasparagine. Rakicidin B differs by one methylene group in the lipid side chain. These compounds exhibited cytotoxicity against the Ml09 cell line.

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A new extended spectrum β-lactamase was detected in Serratia marcescens 42039 that was isolated from urine of patients with complicated urinary tract infection in Japan. This strain produced three different β-lactamase types (TEM-1, a cephalosporinase, and a new β-lactamase: CKH-1). The TEM-1 and CKH-1 encoding genes were conjugated from S. marcescens 42039 to Escherichia coli K-12 at frequencies of 10^-5 to 10^-6. The MICs of β-lactams against the transconjugant were: ampicillin >1600, piperacillin 800, cephalothin 1600, ceftazidime 6.25, cefotaxime 100, and ceftriaxone 200μg/ml. The CKH-1 enzyme was purified to more than 90% by ion-exchange chromatography. The molecular weight of purified CKH-1 was 30 K dalton and the isoelectric point was 8, 2, Relative Vmax/Km values (cephaloridme=100) of penicillin G, cephalothin, and oxyiminocephalosporins such as cefuroxime, ceftriaxone, and cefotaxime, were 256, 226, 116, 87, and 49, respectively. The I₅₀ values of tazobactam, BRL-42715, and clavulanic acid against CKH-1 enzyme were 0.0011, 0.0002, and 0.097μM, respectively. The enzymatic activity of CKH-1 was not inhibited by EDTA and anti-TEM-1 serum. These findings indicate that CKH-1 is a member of the groups of class A β-lactamases. This is the first report of a plasmid-mediated oxyiminocephalosporin hydrolyzing broad-spectrum β-lactamase from clinical isolates of S. marcescens.

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We have synthesized derivatives of dephostatin, a protein tyrosine phosphatase (PTPase) inhibitor, to study the structure-activity relationships of this inhibitor. Inactive analogs revealed some insight into structural requirements for PTPase inhibitory activity of dephostatin. Both a nitroso group and phenolic hydroxyl groups were found to be essential for the inhibitory activity. Among the dephostatin derivatives synthesized, one of the regioisomers of dephostatin showed PTPase inhibitory activity equivalent to that of dephostatin, and also had increased stability.

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New derivatives of spicamycin modified at the fatty acid moieties of the molecule were synthesized and their structure-activity relationships were examined. The antitumor activity was greatly influenced by modification of the fatty acid moieties to tetradecadienoyl or dodecadienoyl analogues exhibiting better antitumor activity against COL-1 human colon cancer xenograft than SPM VIII.

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The synthesis and antibacterial activity of the title compounds having an isoxazolidine ring at the C-2 position are described. These derivatives were synthesized by the 1, 3-dipolar cycloaddition reaction of nitrone with 2-vinyl carbapenems. This 1, 3-dipolar cycloaddition reaction proceeded regioselectively to give diastereomeric isomers of 2-(isoxazolidin-5-yl)carbapenems. It was ascertained that the antibacterial activity of β-methylcarbapenem derivatives was superior to that of the corresponding 1H-carbapenem derivatives, and between the 2-(isoxazolidin-5-yl)-1β-methylcarbapenems the antibacterial activity of the 5'R-isomer was slightly better than that of the 5'S-isomer.

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The antibacterial activities of three new penems with 4-hydroxyprolinamide, 1-prolinamide and N-methyl-N-2-propionamide substituents, respectively, in position 2 and of their stereoisomers were examined against Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Escherichia coli and Pseudomonas aeruginosa. All substituents conferred a broad antibacterial spectrum on the penem moiety. Changes in stereoisomerism selectively improved the activity against E. coli, S. aureus or enterococci. The structure-activity relationships of each compound were discussed in relation to minimum inhibitory concentrations, penicillin-binding protein (PBP) affinity and outer membrane permeability coefficient in E. coli. In this microorganism, PBP 2 was the target for all compounds. Changes in stereoisomerism influenced the affinity for PBPs 1A/B and 2. All antibiotics easily permeated the outer membrane of E. coli and, within each group of compounds, the penetration rate correlated with the antibacterial activity.

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