title: Fungal transformation and T-cell proliferation inhibitory activity of melengestrol acetate and its metabolite.
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 (1)H- and (13)C-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±0.08μg/mL, respectively. The results indicated that these compounds possess sixfold potent T-cell proliferation inhibitory activity as compared to the standard prednisolone (IC50<3.1μg/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.
authors.affiliation: Biology Deparment, American University of Beirut, Beirut 1107 2020, Lebanon. Electronic address: eliasbay@aub.edu.lb.
authors.forename: Elias
authors.initials: E
authors.lastname: Baydoun
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Saira
authors.initials: S
authors.lastname: Bano
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: atia.tulwahab@iccs.edu.
authors.lastname: Atia-tul-Wahab
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Almas
authors.initials: A
authors.lastname: Jabeen
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Sammer
authors.initials: S
authors.lastname: Yousuf
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mesaik
authors.affiliation: Biology Deparment, American University of Beirut, Beirut 1107 2020, Lebanon.
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia.
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Choudhary
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001711:Biotransformation; D049109:Cell Proliferation / Q000187:drug effects; D020093:Cunninghamella / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008552:Melengestrol Acetate / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D008552:Melengestrol Acetate
keywords: Anti-inflammatory; Biotransformation; Cunninghamella blakesleeana; Melengestrol acetate