Fungal mediated biotransformation of melengestrol acetate, and T-cell proliferation inhibitory activity of biotransformed compounds

• Published in: Bioorganic chemistry Vol. 104; pp. 104313 - 104319
• Main Authors: Javed, Saira, Atia-tul-Wahab, Jabeen, Almas, Zhumagaliyeva, Shynar, Abilov, Zharylkasyn A., Atta-ur-Rahman, Choudhary, M. Iqbal
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.11.2020; Elsevier
• Subjects: 3T3 Cells; Animals; Anti-inflammatory; Biochemistry & Molecular Biology; Biotransformation; Cell Proliferation - drug effects; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Fermentation; Humans; Life Sciences & Biomedicine; Melengestrol acetate; Melengestrol Acetate - chemistry; Melengestrol Acetate - metabolism; Melengestrol Acetate - pharmacology; Mice; Molecular Structure; Phyllachorales - chemistry; Phyllachorales - metabolism; Physical Sciences; Rhizopus - chemistry; Rhizopus - metabolism; Science & Technology; Seeds - chemistry; Seeds - metabolism; Structure-Activity Relationship; T-cell Proliferation; T-Lymphocytes - drug effects; T-cell Proliferation; Melengestrol acetate; Anti-inflammatory; Biotransformation; METABOLITES; ECHINULATA; CUNNINGHAMELLA-BLAKESLEEANA; FUSARIUM-LINI; MICROBIAL TRANSFORMATION; MACROPHOMINA-PHASEOLINA; CONTRACEPTIVE DRUG
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104313

[Display omitted] •Fermentation of melengestrol acetate (1) yielded four new derivatives 2–5.•Oxidation and dehydrogenation were occurred during biotransformation.•Compounds 1, 2, 4, and 5 showed a potent activity against T-cell proliferation in vitro.•Compounds 1–5 were inactive to mouse fibroblast 3T3 cell line. Glomerella fusaroide, and Rhizopus stolonifer were effectively able to transform the steroidal hormone melengestrol acetate (MGA) (1) into four (4) new metabolites, 17α-acetoxy-11α-hydroxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione (2), 17α-acetoxy-11α-hydroxy-6-methyl-16-methylenepregna-1,4,6-triene-3,20-dione (3), 17α-acetoxy-6,7α-epoxy-6β-methyl-16-methylenepregna-4,6-diene-3,20-dione (4), and 17α-acetoxy-11β,15β-dihydroxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione (5). All these compounds were structurally characterized by different spectroscopic techniques. The objective of the current study was to assess the anti-inflammatory potential of melengestrol acetate (1), and its metabolites 2–5. The metabolites and the substrate were assessed for their inhibitory effects on proliferation of T-cells in vitro. The substrate (IC50 = 2.77 ± 0.08 µM) and its metabolites 2 (IC50 = 2.78 ± 0.07 µM), 4 (IC50 = 2.74 ± 0.1 µM), and 5 (IC50 = < 2 µM) exhibited potent T- cell proliferation inhibitory activities, while compound 3 (IC50 = 29.9 ± 0.09 µM) showed a moderate activity in comparison to the standard prednisolone (IC50 = 9.73 ± 0.08 µM). All the metabolites were found to be non-toxic against 3T3 normal cell line. This study thus identifies some potent compounds active against T-cell proliferation. Their anti-inflammatory potential, therefore, deserves to be further investigated.