ABSTRACT
A new peptaibol compound, SPF-5506-A4, was isolated from the fermentation broth of Trichoderma sp. SPF-5506. The chemical structure of the 14-residue peptide was determined by MS, NMR and amino acid sequence analyses. The absolute configuration of amino acid residues in the acid hydrolysate was determined by Marfey's method. The structure of SPF-5506-A4 was established as Ac-Aib-L-Asn-L-Ile-Aib-L-Pro-L-Ser-L-Ile-Aib-L-Pro-L-Leu-L-Leu-Aib-L-Pro-L-leucinol. The compound inhibited amyloid beta-peptide formation in primary guinea pig cerebral cortex neuron cell culture dose-dependently with an IC50 of 0.1 microg/ml. Cytotoxicity was not observed at concentrations of <3 microg/ml.
Subject(s)
Amyloid beta-Peptides/biosynthesis , Cerebral Cortex/drug effects , Neurons/drug effects , Oligopeptides/pharmacology , Peptides/chemistry , Peptides/metabolism , Trichoderma/metabolism , Amino Acid Sequence , Amyloid beta-Peptides/metabolism , Animals , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Fermentation , Guinea Pigs , Mass Spectrometry , Molecular Sequence Data , Neurons/metabolism , Oligopeptides/biosynthesis , Peptides/pharmacology , Trichoderma/classification , Trichoderma/growth & developmentABSTRACT
Two new human chymase inhibitors, SPF-32629A and B, were isolated from the cultured broth of Penicillium sp. SPF-32629. These structures were determined by spectroscopic methods and identified as new pyridone compounds. SPF-32629B was the carboxylated derivative of SPF-32629A. SPF-32629A and B specifically inhibited human chymase among four serine proteases tested with the IC50 of 0.25 and 0.42 microg/ml, respectively.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Niacin/analogs & derivatives , Penicillium/metabolism , Protease Inhibitors/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Serine Endopeptidases/metabolism , Antibiotics, Antineoplastic/biosynthesis , Cell Survival/drug effects , Chemical Phenomena , Chemistry, Physical , Chromatography, High Pressure Liquid , Chymases , Fermentation , HL-60 Cells , Humans , Magnetic Resonance Spectroscopy , Molecular Conformation , Niacin/chemistry , Penicillium/classification , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, UltravioletABSTRACT
Two new 24-membered macrolides, SPA-6952A and B, were isolated from the fermentation broth of Streptomyces sp. SPA-6952. The structures of the new macrolides were determined by spectral analyses, including 2D NMR techniques. These compounds exhibited cytotoxic activity against human promyelocytic leukemia HL-60 cells.
Subject(s)
Antibiotics, Antineoplastic/biosynthesis , Macrolides/metabolism , Streptomyces/metabolism , Antibiotics, Antineoplastic/isolation & purification , Antibiotics, Antineoplastic/pharmacology , Chromatography, High Pressure Liquid , Fermentation , HL-60 Cells , Humans , Macrolides/isolation & purification , Macrolides/pharmacology , Molecular Conformation , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, Infrared , Spectrophotometry, UltravioletABSTRACT
Seven new antimycin antibiotics, named antimycins A10, A11, A12, A13, A14, A15 and A16, were isolated from the fermentation broth of strains of Streptomyces spp. SPA-10191 and SPA-8893, along with known antimycins A1, A2, A3 and A4. The structures of the new antimycins were determined by spectral analyses, including 2D NMR techniques. These compounds exhibited antifungal activity against Candida utilis.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Antifungal Agents/isolation & purification , Antimycin A/analogs & derivatives , Streptomyces/classification , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida/drug effects , Fermentation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A new semaphorin inhibitor xanthofulvin was isolated from the cultured broth of a fungus Penicillium sp. SPF-3059 along with a known compound vinaxanthone by solvent extraction and bioassay-guided fractionation. The tautomeric structure of xanthofulvin was determined by spectroscopic analyses. The two compounds exhibited significant semaphorin inhibitory activity with IC50 values of 0.09 and 0.1 microg/ml, respectively, in semaphorin3A-induced growth cone collapse assay using cultured chick dorsal root ganglia neurons.
Subject(s)
Chromones , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Penicillium/metabolism , Semaphorin-3A/antagonists & inhibitors , Xanthenes/chemistry , Xanthones , Animals , Chick Embryo , Enzyme Inhibitors/isolation & purification , Fermentation , Ganglia, Spinal/drug effects , Ganglia, Spinal/enzymology , Growth Cones/metabolism , Microscopy, Electron, Scanning , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Penicillium/chemistry , Semaphorin-3A/metabolism , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Xanthenes/isolation & purification , Xanthenes/pharmacologyABSTRACT
SM-216289 (xanthofulvin) isolated from the fermentation broth of a fungal strain, Penicillium sp. SPF-3059, was identified as a strong semaphorin 3A (Sema3A) inhibitor. Sema3A-induced growth cone collapse of dorsal root ganglion neurons in vitro was completely abolished in the presence of SM-216289 at levels less than 2 mum (IC50 = 0.16 mum). When dorsal root ganglion explants were co-cultured with Sema3A-producing COS7 cells in a collagen gel matrix, SM-216289 enabled neurites to grow toward the COS7 cells. SM-216289 diminished the binding of Sema3A to its receptor neuropilin-1 in vitro, suggesting a direct interference of receptor-ligand association. Moreover, our data suggest that SM-216289 interacted with Sema3A directly and blocked the binding of Sema3A to its receptor. We examined the efficacy of SM-216289 in vivo using a rat olfactory nerve axotomy model, in which strong Sema3A induction has been reported around regenerating axons. The regeneration of olfactory nerves was significantly accelerated by a local administration of SM-216289 in the lesion site, suggesting the involvement of Sema3A in neural regeneration as an inhibitory factor. SM-216289 is an excellent molecular probe to investigate the function of Sema3A, in vitro and in vivo, and may be useful for the treatment of traumatic neural injuries.
