A novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, designated epi-cochlioquinone A has been isolated from the fermentation broth of Stachybotrys bisbyi SANK 17777. The molecular formula, physicochemical properties, NMR spectroscopic analysis and X-ray crystallographic analysis revealed that this compound was a stereoisomer of cochlioquinone A, which has been previously reported as a nematocidal agent. It inhibited ACAT activity in an enzyme assay using rat liver microsomes with an IC₅₀ value of 1.7μM. However, it showed about 10-fold less potent inhibitory effect on plasma lecithin cholesterol acyltransferase (LCAT) than on ACAT. In addition, it inhibited in vivo cholesterol absorption in rats by 50% at 75mg/kg.

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New protein farnesyltransferase inhibitors, andrastins A-C, have been discovered in the cultured broth of Penidllium sp. FO-3929. Andrastins extracted from broth supernatant were purified by silica gel chromatography, ODS chromatography and HPLC. The IC₅₀ of andrastins A, B, and C against protein farnesyltransferase were 24.9, 47.1, and 13.3μM, respectively.

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The structures of new protein farnesyltransferase inhibitors, andrastins A-C, were elucidated. The cyclopentane ring of andrastins exhibited keto-enol tautomerism, which made the structure hard to elucidate. Therefore, the structure of andrastin A was elucidated by INADEQUATE and ¹³C-¹³C couplings using ¹³C-labeled andrastin A. The absolute configuration of the p-bromobenzoyl derivative of andrastin A was elucidated by X-ray crystallographic analysis and its skeleton was shown to be ent-5α, 14β-androstane. The biosynthesis of andrastin A was also studied by the incorporation of ¹³C-labeled acetates. Though the andrastins had a common androstane skeleton, they were biosynthesized from a sesquiterpene and a tetraketide.

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New ansamycins designated hydroxymycotrienins A and B were isolated from culture broths of Bacillus sp. BMJ958-62F4. The two antibiotics inhibited more strongly the growth of human cervical cancer cell lines of human papilloma virus (HPV) positive than that of HPV negative cell lines. The structures, some biological and biochemical properties are reported.

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Chemical screening using thin layer chromatography and various staining reagents offers the opportunity to visualize a nearly complete picture of a microbial secondary metabolite pattern (metabolic finger-print). This approach can be used advantageously for both, the detection of so-called "talented" strains, and for qualifying microbial strain collections, especially as a fundamental step of efficiently applied biological high-throughput assays. Based on their metabolic finger-print, microbial isolates can be classified in: (i) non-producing organisms, which gave no indication of the formation of secondary metabolites up to a defined detection limit, (ii) organisms of narrow productivity, which produce one or two secondary metabolites as main products with a restricted dependance to alteration of the culture conditions, and (iii) talented organisms, which are able to synthesize an array of structurally different secondary metabolites. As an example, the talented strain, Streptomyces griseoviridis (FH-S 1832), was studied in detail. Investigations in its taxonomical characterization, fermentation, as well as the isolation and purification procedures leading to 14-membered macrocyclic lactones of the cineromycin-type (cineromycin B and three new congeners) and to the musacins A to F are reported. Musacin C exhibits anthelminthic and weak antiviral activities.

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A detailed analysis of the secondary metabolite pattern produced by Streptomyces griseoviridis (strain FH-S 1832) using a chemical screening method resulted in the detection, isolation and structure elucidation of new 14-membered lactones of the cineromycin B-type [dehydrocineromycin B (5), oxycineromycin B (7), and 2, 3-dihydrocineromycin B (8)], as well as new γ-lactones related to nigrosporalactone and 4, 5-dihydroxy-octa-2, 6-dienoic acid esters named musacins A to F (10, 13-15, 17, 18 and 21). The constitution of these metabolites were deduced from spectroscopic data as well as chemical transformations. The configuration of musacin D (10) was determined by derivatization with chiral acids (Helmchen's method).

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Five new minor metabolites, papyracon D (6), 6-O-methylpapyracon B (9), 6-O-methylpapyracon C (10), lachnumfuran A (11) and lachnumlactone A (12a), together with the known chloromycorrhizinol A (4), have been isolated from extracts of the culture fluids of the ascomycete Lachnum papyraceum. The compounds, which structures were determined by spectroscopic methods, are structurally related to the nematicidal and antibiotic mycorrhizin A (1), which also is produced by the fungus. The nematicidal, antibiotic and cy to toxic activities of the new compounds are weaker compared to those of mycorrhizin A (1). Papyracon D (6) possesses the highest antibiotic activities while lachnumlactone A (12a) is the most nematicidal and cytotoxic.

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During screening for inhibitors of T cell activation, we have found that trichostatin A (TSA), known as a potent inhibitor of histone deacetylase, showed selective inhibitory activity against IL-2 gene expression. From luciferase reporter experiments on human leukemic Jurkat T cells, TSA was found to inhibit the expression of the luciferase reporter gene directed by the IL-2 enhancer and promoter with a 50% inhibitory concentration value of 0.073 μM. On the other hand, TSA, at the same concentration, enhanced the expression of the luciferase reporter gene directed by the c-fos enhancer and promoter. The result of RT-PCR experiments also indicates that TSA has selective inhibitory activity against IL-2 gene expression in Jurkat cells. These results suggest that the change in chromatin structure caused by the hyperacetylation of histone might affect the regulation of IL-2 and c-fos gene expression.

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Aminoglycoside antibiotics (AGs) with a free 2'-amino group were subjected to enzymatic N-acetylation using a cell free extract that contained an aminoglycoside 2'-N-acetyltransferase, AAC (2'), derived from a kasugamycin-producing strain of Streptomyces kasugaensis. TLC and antibiotic assay of the incubated reaction mixtures revealed that a modified compound retaining substantial antibiotic activity was formed from arbekacin (ABK), while modification of the other AGs resulted in the marked decrease in antibiotic activity. Structure determination following isolation from a large scale reaction mixture showed the modified ABK to be 2'-N-acetyl ABK. In addition, 2', 6'-di-N-acetyl ABK was formed as a minor product. The same conversion also occurred with dibekacin (DKB) resulting in the formation of 2'-N-acetyl DKB and 2', 6'-di-N-acetyl DKB. MIC determination showed antibacterial activity (1.56-3.13 μg/ml) of 2'-N-acetyl ABK against a variety of organisms. By contrast, 2'-N-acetyl DKB showed no substantial antibiotic activity. We believe 2'-N-acetyl ABK has the highest and broadest antibacterial activity, compared with known N-acetylated AGs.

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The 11, 12-cyclic carbazate of 3-keto-6-O-methylerythromycin A (4) was prepared. This compound shows in vitro antibacterial activity comparable to erythromycin A (1) against erythromycin-susceptible organisms and increased activity against some erythromycin-resistant organisms. Using 4 as a lead, a series of analogues was prepared by acylation or alkylation of the carbazate nitrogen. Several of the N-alkylated derivatives showed dramatically improved antibacterial activity against both susceptible and resistant organisms as compared to erythromycin A.

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We describe an efficient method for introducing a sulfamoylamino group into the C-2' position of pyrrolidine using the Mitsunobu reaction. S-4661, its N-methyl analogues and stereoisomers were synthesized using this method and their structure-activity relationships were investigated.

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