Fungal transformation and T-cell proliferation inhibitory activity of melengestrol acetate and its metabolite
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Elsevier Inc.
Abstract
Biotransformation of melengestrol acetate (MGA, 17α-acetoxy-6-methyl- 16-methylenepregna-4,6-diene-3,20-dione) (1) was investigated for the first time by using fungal cultures. Incubation of compound 1 with Cunninghamella blakesleeana yielded a new major metabolite, 17α-acetoxy-11β-hydroxy- 6-methyl-16-methylenepregna-4,6-diene-3,20-dione (2). The metabolite 2 was purified by using HPLC, followed by characterization through 1H- and 13C-NMR and other spectroscopic techniques. Single crystal X-ray diffraction analysis was used to deduce the three dimensional structures of melengestrol acetate (1) and metabolite 2 for the first time. T-cell proliferation assay was employed to evaluate the immunosuppressant effect of compounds 1 and 2 with IC50 = 0.5 ± 0.07 and 0.6 ± 0.08 μg/mL, respectively. The results indicated that these compounds possess sixfold potent T-cell proliferation inhibitory activity as compared to the standard prednisolone (IC50 < 3.1 μg/mL). Both compounds were found to be non-toxic in a 3T3 (mouse fibroblast) cell-based cytotoxicity assay. This discovery of potent anti-inflammatory activity of compounds 1 and 2 can lead the way to develop new immunosuppressant compounds for clinical application. © 2014 Elsevier Inc. All rights reserved.
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Keywords
Anti-inflammatory, Biotransformation, Cunninghamella blakesleeana, Melengestrol acetate, 3t3 cells, Animals, Anti-inflammatory agents, non-steroidal, Cell proliferation, Cunninghamella, Dose-response relationship, drug, Immunosuppressive agents, Mice, Models, molecular, Molecular conformation, Structure-activity relationship, T-lymphocytes, 17alpha acetoxy 11beta hydroxy 6 methyl 16 methylenepregna 4, 6 diene 3,20 dione, Antiinflammatory agent, Immunosuppressive agent, Prednisolone, Unclassified drug, Nonsteroid antiinflammatory agent, Animal cell, Antiinflammatory activity, Article, Controlled study, Drug cytotoxicity, Drug hydroxylation, Drug transformation, Fermentation, Fungal phenomena and functions, Fungal transformation, Ic 50, Lymphocyte proliferation, Molecular interaction, Mouse, Nonhuman, Stereochemistry, T lymphocyte, X ray diffraction, 3t3 cell line, Animal, Chemical structure, Chemistry, Conformation, Cytology, Dose response, Drug effects, Metabolism, Structure activity relation