Five new asterriquinone analogs (2-4, 6, 7), together with previously identified neoasterriquinone (1) and isoasterriquinone (5), were isolated from a fermentation broth of the fungus Aspergillus candidus and purified by HSCCC (high speed counter current chromatography) followed by HPLC. The structures were determined by ID and 2D NMR and MS/MS techniques. All seven showed inhibitory activity against the binding of a recombinant protein containing the SH2 protein domain of Grb-2 to the tyrosine phosphorylated form of the EGF receptor tyrosine kinase. Some of these asterriquinones exhibited specific inhibition of Grb-2 binding compared to Grb-7 and PLC-γ.

View full abstract

During the course of our screening program for low molecular natural products with their ability to potentiate and/or mimic neurotrophic effect of NGF, a novel fungal metabolite, phenylacetic acid hydrazide derivative NG-061 was isolated from the fermentation broth of Penicillium minioluteum F-4627. NG-061 enhanced and mimicked neurotrophic effect of NGF on neurite outgrowth in a rat pheochromocytoma cell line PC 12.

View full abstract

The structure of NG-061, a new potentiator of nerve growth factor (NGF) isolated from Penicillium minioluteum F-4627, was determined by spectroscopic analysis and X-ray diffraction method to be phenylacetic acid 2-(2-methoxy-4-oxocyclohexa-2, 4-dienylidene)-hydrazide.

View full abstract

Nine azaphilones designated RP-1551-1, -2, -3, -4, -5, -6, -7, -M1, and -M2 were isolated from the culture broth of Penicillium sp. SPC-21609 as inhibitors of PDGF binding to its receptor. RP-1551s inhibit the binding of PDGF AA to the extracellular domain of PDGF α-receptor with IC₅₀ values ranging from 0.1 to 2μM without affecting PDGF BB binding to the extracellular domain of PDGF β-receptor. PDGF binding was not restored after the PDGF α-receptor extracellular domain was washed in an attempt to remove the RP-1551-1 bound to the receptor. This result suggests that RP-1551-1 may irreversibly interact with the PDGF α-receptor. Since many azaphilone compounds possess high reactivity with an aminol group, RP-1551-1 may prevent PDGF AA binding by reacting with amino groups on the α-receptor extracellular domain.

View full abstract

During the screening of the natural products for their ability to increase the activity of glucokinase by relieving inhibition by long chain fatty acyl CoA esters (FAC), two novel compounds, glucolipsin A (1) and B (2) were isolated from the butanol extracts of Streptomyces purpurogeniscleroticus WC71634 and Nocardia vaccinii WC65712, respectively. The structures of these two compounds were established by spectroscopic methods and chemical degradation. Glucolipsin A (1) and B (2) relieved the inhibition of glueokinase by FAC with RC₅₀ values of 5.4 and 4.6μM.

View full abstract

Cdc25A assay-guided fractionation of a fermentation broth derived from a Streptomyces sp. resulted in the isolation of four novel naphthoquinones 1-4. Structures of these compounds were deduced by NMR and mass spectrometry. Two of them, 3 and 4, incorporate a modified cysteine residue which is observed for the first time in this class of natural products. Naphthoquinones 1-4 showed weak activity against cdc25A phosphatase.

View full abstract

A new antitumor antibiotic gilvusmycin was isolated from the culture broth of Streptomyces sp. QM16. The structure of gilvusmycin was related to CC-1065 and determined by NMR spectral analysis. Gilvusmycin exhibited antitumor activity against murine leukemia P388 in vivo.

View full abstract

Lactonamycin (1) was isolated from a culture broth of Streptomyces rishiriensis MJ773-88K4. Antibiotic 1 exhibited antimicrobial activities against Gram-positive bacteria including methicillin-resistant Staphylocoecus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).

View full abstract

The absolute structure of a new antibiotic lactonamycin is described. The NMR studies deduced one of four possible structures for the aglycon attached by a rhodinose through glycosidic bond. The stereochemistry of the sugar obtained by an acid hydrolysis was determined to be L-form by measuring optical rotation. The stereochemistry of the aglycon was determined by X-ray crystallographic analysis.

View full abstract

The structures of the fatty acid components of various new liposidomycins were determined using tandem mass Spectrometry; the negative FAB/MS/MS/MS technique for liposidomycins with a 3-methylglutaric acid moiety and the negative FAB/MS/MS technique for liposidomycins without a 3-methylglutaric acid moiey. This structural information was obtained by analysis of peaks due to charge-remote fragmentations for 3-hydroxycarboxylate anions or carboxylate anions which were generated from liposidomycin molecules in a mass spectrometer. The MS/MS/MS technique that can exclude the matrix-derived and/or interfering ions showed higher sensitivity than the MS/MS technique.

View full abstract

The tlrB gene, which confers inducible resistance to a range of macrolide antibiotics including biosynthetic precursors of tylosin, was isolated and sequenced. In the genome of Streptomyces fradiae, it lies between pbp, which encodes a putative penicillin-binding protein, and tylN, encoding a glycosyltransferase involved in tylosin biosynthesis. The TlrB protein was produced in E. coli as a fusion to MalE. The fusion protein, but not MalE alone, inactivates macrolides in the presence of S-adenosyl-methionine (SAM) but the modified product(s) has not been characterised.

View full abstract

Immunosuppressant 15-deoxyspergualin (DSG) inhibited induction of inducible nitric oxide synthase (iNOS) following stimulation with IFN-γ and LPS in a cultured macrophage cell line, J744A.1. By DSG treatment NQ^2- accumulation in the medium was blocked, and cellular iNOS protein level decreased as shown by Western blotting.
DSG didn't have any direct effect on iNOS activity. DSG was not used as a substrate of NOS in in vitro enzyme systems, and it was too weak an inhibitor of iNOS and cNOS to cause the inhibition of accumulation of NO^2-. DSG did not scavenge NO spontaneously generated from NOR.
Structure-activity relationships of analogs and decomposed elements showed that there is correlation between the inhibition of iNOS induction and immunosuppressive activity.

View full abstract

Mulundocandin (MCN) is an antifungal lipopeptide which belongs to the echinocandin class of antimycotic agents. MCN exhibited good in vitro activity against Candida albicans and C. glabrata isolates with MIC ranges of 0.5-4.0μg/ml and 2.0-4.0μg/ml, respectively. MCN also exhibited some activity against C. tropicalis isolates (MIC range 1.0-8.0μg/ml). However, MCN was poorly active against other non-albicans isolates and was inactive against Cryptococcus neoformans, Aspergillus species and Triehophyton. MCN appeared to exert its antifungal activity through preferential inhibition of germ tube formation (MIC-HY 0.015-0.03μg/ml) and was typically less active on the yeast form (MIC 0.5-4.0μg/ml). In kill-curve experiments 99.9% reductions in cell viability were observed following 8 hours exposure to MCN at 4 × MIC and 8 × MIC and after 5 hours exposure to 16 × MIC.

View full abstract

Aspirochlorine, a compound belonging to the gliotoxin family of compounds, exhibits antifungal and antibacterial activity but its mechanism of action remains unknown. In this study we show that aspirochlorine inhibits the pathogenic fungus Candida albicans by acting on fungal protein synthesis. The compound selectively inhibits cell-free protein synthesis when using a C. albicans system, but does not inhibit this synthesis in vitro when tested with bacterial and mammalian systems. Moreover, in intact C. albicans cells, aspirochlorine inhibits protein synthesis but does not inhibit chitin, DNA or glucan synthesis though at high concentrations some inhibition of RNA synthesis is observed. By contrast, in intact Bacillus subtilis cells, aspirochlorine did not inhibit protein, DNA, or cell wall synthesis though it significantly inhibited RNA synthesis. Furthermore, using heterologous systems (mammalian ribosomes and C. albicans cytosolic factors) the data suggest that the inhibitory action of aspirochlorine is not exerted through a direct interaction with C. albicans EF-1 or EF-2.

View full abstract

AA3-Carboxyeremomycin 2, obtained by selective hydrolysis of antibiotic eremomycin was used as a starting compound for the eremomycin chemical modifications at the asparagine side chain to be transformed into eremomycin AA3, AA7 bis-amides (3a-c). Bis-benzylamide 3b displayed an activity (8μg/ml) against an E. faecium VanA strain.

View full abstract