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New Anti-Inflammatory Metabolites by Microbial Transformation of Medrysone.

ABSTRACT: Microbial transformation of the anti-inflammatory steroid medrysone (1) was carried out for the first time with the filamentous fungi Cunninghamella blakesleeana (ATCC 8688a), Neurospora crassa (ATCC 18419), and Rhizopus stolonifer (TSY 0471). The objective was to evaluate the anti-inflammatory potential of the substrate (1) and its metabolites. This yielded seven new metabolites, 14?-hydroxy-6?-methylpregn-4-ene-3,11,20-trione (2), 6?-hydroxy-6?-methylpregn-4-ene-3,11,20-trione (3), 15?-hydroxy-6?-methylpregn-4-ene-3,11,20-trione (4), 6?,17?-dihydroxy-6?-methylpregn-4-ene-3,11,20-trione (5), 6?,20S-dihydroxy-6?-methylpregn-4-ene-3,11-dione (6), 11?,16?-dihydroxy-6?-methylpregn-4-ene-3,11-dione (7), and 15?,20R-dihydroxy-6?-methylpregn-4-ene-3,11-dione (8). Single-crystal X-ray diffraction technique unambiguously established the structures of the metabolites 2, 4, 6, and 8. Fungal transformation of 1 yielded oxidation at the C-6?, -11?, -14?, -15?, -16? positions. Various cellular anti-inflammatory assays, including inhibition of phagocyte oxidative burst, T-cell proliferation, and cytokine were performed. Among all the tested compounds, metabolite 6 (IC50 = 30.3 ?g/mL) moderately inhibited the reactive oxygen species (ROS) produced from zymosan-induced human whole blood cells. Compounds 1, 4, 5, 7, and 8 strongly inhibited the proliferation of T-cells with IC50 values between <0.2-10.4 ?g/mL. Compound 7 was found to be the most potent inhibitor (IC50 < 0.2 ?g/mL), whereas compounds 2, 3, and 6 showed moderate levels of inhibition (IC50 = 14.6-20.0 ?g/mL). Compounds 1, and 7 also inhibited the production of pro-inflammatory cytokine TNF-?. All these compounds were found to be non-toxic to 3T3 cells (mouse fibroblast), and also showed no activity when tested against HeLa (human epithelial carcinoma), or against PC3 (prostate cancer) cancer cell lines.

SUBMITTER: Bano S

PROVIDER: S-EPMC4841542 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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New Anti-Inflammatory Metabolites by Microbial Transformation of Medrysone.

Bano Saira S Wahab Atia-Tul- AT Yousuf Sammer S Jabeen Almas A Mesaik Mohammad Ahmed MA Rahman Atta-Ur- AU Choudhary M Iqbal MI

PloS one 20160422 4

Microbial transformation of the anti-inflammatory steroid medrysone (1) was carried out for the first time with the filamentous fungi Cunninghamella blakesleeana (ATCC 8688a), Neurospora crassa (ATCC 18419), and Rhizopus stolonifer (TSY 0471). The objective was to evaluate the anti-inflammatory potential of the substrate (1) and its metabolites. This yielded seven new metabolites, 14α-hydroxy-6α-methylpregn-4-ene-3,11,20-trione (2), 6β-hydroxy-6α-methylpregn-4-ene-3,11,20-trione (3), 15β-hydroxy ...[more]

PMID: 27104348

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Project description:BackgroundBiotransformation of organic compounds by using microbial whole cells provides an efficient approach to obtain novel analogues which are often difficult to synthesize chemically. In this manuscript, we report for the first time the microbial transformation of a synthetic anabolic steroidal drug, oxymetholone, by fungal cell cultures.ResultsIncubation of oxymetholone (1) with Macrophomina phaseolina, Aspergillus niger, Rhizopus stolonifer, and Fusarium lini produced 17?-hydroxy-2-(hydroxy-methyl)-17?-methyl-5?-androstan-1-en-3-one (2), 2?,17?-di(hydroxyl-methyl)-5?-androstan-3?,17?-diol (3), 17?-methyl-5?-androstan-2?,3?,17?-triol (4), 17?-hydroxy-2-(hydroxymethyl)-17?-methyl-androst-1,4-dien-3-one (5), 17?-hydroxy-2?-(hydroxy-methyl)-17?-methyl-5?-androstan-3-one (6), and 2?-(hydroxymethyl)-17?-methyl-5?-androstan-3?-17?-diol (7). Their structures were deduced by spectral analyses, as well as single-crystal X-ray diffraction studies. Compounds 2-5 were identified as the new metabolites of 1. The immunomodulatory, and anti-inflammatory activities and cytotoxicity of compounds 1-7 were evaluated by observing their effects on T-cell proliferation, reactive oxygen species (ROS) production, and normal cell growth in MTT assays, respectively. These compounds showed immunosuppressant effect in the T-cell proliferation assay with IC50 values between 31.2 to 2.7 ?g/mL, while the IC50 values for ROS inhibition, representing anti-inflammatory effect, were in the range of 25.6 to 2.0 ?g/mL. All the compounds were found to be non-toxic in a cell-based cytotoxicity assay.ConclusionMicrobial transformation of oxymetholone (1) provides an efficient method for structural transformation of 1. The transformed products were obtained as a result of de novo stereoselective reduction of the enone system, isomerization of double bond, insertion of double bond and hydroxylation. The transformed products, which showed significant immunosuppressant and anti-inflammatory activities, can be further studied for their potential as novel drugs.

Project description:The frequent re-isolation of known compounds is one of the major challenges in drug discovery. Many biosynthetic genes are not expressed under standard culture conditions, thus limiting the chemical diversity of microbial compounds that can be obtained through fermentation. On the other hand, the competition during co-cultivation of two or more different microorganisms in most cases leads to an enhanced production of constitutively present compounds or an accumulation of cryptic compounds that are not detected in axenic cultures of the producing strain under different fermentation conditions. Herein, we report the dual induction of newly detected bacterial and fungal metabolites by the co-cultivation of the marine-derived fungal isolate Aspergillus fumigatus MR2012 and two hyper-arid desert bacterial isolates Streptomyces leeuwenhoekii strain C34 and strain C58. Co-cultivation of the fungal isolate MR2012 with the bacterial strain C34 led to the production of luteoride D, a new luteoride derivative and pseurotin G, a new pseurotin derivative in addition to the production of terezine D and 11-O-methylpseurotin A which were not traced before from this fungal strain under different fermentation conditions. In addition to the previously detected metabolites in strain C34, the lasso peptide chaxapeptin was isolated under co-culture conditions. The gene cluster for the latter compound had been identified through genome scanning, but it had never been detected before in the axenic culture of strain C34. Furthermore, when the fungus MR2012 was co-cultivated with the bacterial strain C58, the main producer of chaxapeptin, the titre of this metabolite was doubled, while additionally the bacterial metabolite pentalenic acid was detected and isolated for the first time from this strain, whereas the major fungal metabolites that were produced under axenic culture were suppressed. Finally, fermentation of the MR2012 by itself led to the isolation of the new diketopiperazine metabolite named brevianamide X.

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New Anti-Inflammatory Metabolites by Microbial Transformation of Medrysone.

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New Anti-Inflammatory Metabolites by Microbial Transformation of Medrysone.

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