New5-lipoxygenase inhibitors, designated epocarbazolins A and B, were isolated from the culture broth of Streptomyces anulatus T688-8. These compoundsshowedpotent rat 5-lipoxygenase inhibitory activity with weak antibacterial activity. Structural studies revealed that epocarbazolins are new carbazole antibiotics having a novel substitution pattern and an epoxide in the side chain.It is widely known that arachidonic acid-metabolites products, particularly the arachidonate 5-lipoxygenase (5-LPO) metabolites, are observed as chemical mediators in certain inflammatory and allergic states. Moreover, arachidonic acid and its oxidation products were found in psoriatic skin at increased concentrations.1* Accordingly, 5-LPO inhibitors which block the production of such chemical mediators are expected to be useful for the therapeutic treatment of allergies and inflammations such as asthma, psoriasis and hypersensitivity.In the course of screening for 5-LPO inhibitors using RBL-1 enzyme, an actinomycete strain identified as Streptomyces anulatus T688-8 was found to produce novel 5-LPO inhibitors, designated epocarbazolins A and B.
Lagunamycin, a novel 5-lipoxygenase inhibitor, was isolated from the culture broth of Streptomyces sp. AA0310. This compoundshowed potent rat 5-lipoxygenase inhibitory activity (IC50 6.08 um) without lipid peroxidation.As previously described,1~3) a 5-lipoxygenase (5-LPO) inhibitor screen which was composed of a rat 5-lipoxygenase assay and an automated HPLCsystem were successfully employed for analysis of new 5-LPO inhibitory compounds in fermentation broths. In the continued search for 5-LPO inhibitors, Streptomyces sp. AA0310was found to produce a new antibiotic designated lagunamycin. Lagunamycin was produced in good yield by addition of high porous polymer resin in fermentation medium. The active principle was effectively extracted with ethyl acetate from the fermentation broth under acidic conditions and purified by silica gel column chromatography followed by reversed phase silica gel column chromatography. Lagunamycin belonged to a novel family of antibiotics containing a diazo group with potent inhibition against RBL-1 cell's 5-LPO without lipid peroxidation. In this paper, the taxonomy of the producing organism, fermentation, isolation, physico-chemical properties and biological activities of lagunamycin are reported.
Materials and MethodsTaxonomy
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