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Lagunamycin, a novel 5-lipoxygenase inhibitor, was isolated from the culture broth of Streptomyces sp. AA0310. This compound showed potent rat 5-lipoxygenase inhibitory activity (IC50 6.08 microM) without lipid peroxidation.

Three new 5-lipoxygenase inhibitors, designated as BU-4601 A, B and C, were found in the fermentation broth of Streptomyces sp. strain No. AA2807. Their structures were identified as isodecyl, isoundecyl and isolauryl esters of 5-hydroxyanthranilic acid, respectively. Based on their structures, five related esters were synthesized and evaluated for biological activity as inhibitors of 5-lipoxygenase. Both naturally-occurring and chemically-synthesized compounds exhibited almost equal levels of 5-lipoxygenase inhibitory activities in vitro.

Ten metabolites produced by 4 mutants derived from Actinomadura verrucosospora subsp. neohibisca E-40, a high pradimicins producer, were isolated and their structures were determined. Strain JN-219 produced 3 novel analogs of the pradimicin A aglycone, i.e. 11-O-demethyl-7-methoxypradinone II and 11-O-demethylpradinones I and II together with a known aglycone analog, pradinone I, while the metabolites from strain JN-47 were determined to be 2 new aglycone analogs, 11-O-demethylpradimicinone I and 11-O-demethyl-7-methoxypradimicinone II and a known aglycone analog, 11-O-demethylpradimicinone II (11dM-PMN II). Products of strain JN-207 were identified as 11-O-demethyl-6-deoxypradinone I and 11dM-PMN II. Interestingly, a new pradimicin analog, 7-hydroxypradimicin A was isolated from strain JN-58 together with a new aglycone analog, pradimicinone II and 11dM-PMN II. None of these metabolites showed antifungal activity.

The biosynthetic pathway of the pradimicin-benanomicin family of antibiotics was investigated by using sinefungin and blocked mutants derived from Actinomadura verrucosospora subsp. neohibisca E-40 (a high pradimicin producer) or Actinomadura sp. AB1236 (a benanomicin producer). Addition of sinefungin to strain E-40, pradimicin A aglycone-producing mutant or strain AB1236 inhibited the formation of 11-O-demethyl-7-methoxypradinone II (11dM-7M-PN II), resulting in the accumulation of 11-O-demethylpradimicinone II and pradimicinone II. By feeding pradimicin A aglycone and its analogs to mutants blocked early in pradimicin or benanomicin biosynthesis, the following results were obtained: 11-O-demethylpradinone II, 11dM-7M-PN II 11-O-demethylpradinone I, 11-O-demethylpradimicinone I and pradimicinone I were converted to pradimicin A or benanomicin A; the remaining 6 aglycone analogs were not incorporated into the antibiotics. Pradimicin B, dexylosylpradimicin C and dexylosylbenanomicin A were converted to pradimicin A, pradimicin C and benanomicin A, respectively. A biosynthetic pathway for the antibiotics is proposed.

Pradimicins T1 and T2, new members of the pradimicin family of antibiotics, were produced by an actinomycete strain AA3798. Pradimicin T1 exhibited potent activity against a wide spectrum of fungi in vitro and demonstrated efficacy against systemic Candida albicans and Aspergillus fumigatus infections in mice.

BMS-181184 is a new semisynthetic pradimicin derivative with a broad-spectrum antifungal activity. In a search for actinomycetes producing BMS-181184, 4 strains of Actinomadura sp. isolated from soil samples were found to produce the antibiotic under conditions of directed biosynthesis. Among them, Actinomadura sp. AB1236 proved most useful in the production of BMS-181184 when fermented in a medium containing D-serine and D-cycloserine. A minor product isolated from the broth of strain AB1236 was identified as the dexylosyl analog of BMS-181184, which was also obtained by acid hydrolysis of BMS-181184.