title: Reversible Photohydration of Trenbolone Acetate Metabolites: Mechanistic Understanding of Product-to-Parent Reversion through Complementary Experimental and Theoretical Approaches.
abstract: Photolysis experiments (in H2O and D2O) and quantum chemical calculations were performed to explore the pH-dependent, reversible photohydration of trenbolone acetate (TBA) metabolites. Photohydration of 17α-trenbolone (17α-TBOH) and 17β-trenbolone (17β-TBOH) occurred readily in simulated sunlight to yield hydrated products with incorporated H(+) at C4 and OH(-) at either C5 (5-OH-TBOH) or C12 (12-OH-TBOH) in the tetracyclic steroid backbone. Although unable to be elucidated analytically, theory suggests preferred orientations of cis-12-OH-TBOH (relative to C13 methyl) and trans-5-OH-TBOH, with the former most thermodynamically stable overall. Both experiment and theory indicate limited stability of trans-5-OH-TBOH at acidic pH where it undergoes concurrent, carbocation-mediated thermal rearrangement to cis-12-OH-TBOH and dehydration to regenerate its parent structure. Experiments revealed cis-12-OH-TBOH to be more stable at acidic pH, which is the only condition where its reversion to parent TBA metabolite occurred. At basic pH cis-12-OH-TBOH decayed quickly via hydroxide/water addition, behavior that theory attributes to the formation of a stable enolate resistant to dehydration but prone to thermal hydration. In a noteworthy deviation from predicted theoretical stability, 17α-TBOH photohydration yields major trans-5-OH-TBOH and minor cis-12-OH-TBOH, a distribution also opposite that observed for 17β-TBOH. Because H(+) and OH(-) loss from adjacent carbon centers allows trans-5-OH-TBOH to dehydrate at all pH values, the presumed kinetically controlled yield of 17α-TBOH photohydrates results in a greater propensity for 17α-TBOH reversion than 17β-TBOH. Additional calculations explored minor, but potentially bioactive, trenbolone analogs that could be generated via alternative rearrangement of the acidic carbocation intermediate.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Lehigh University , B336 Iacocca Hall, 111 Research Drive, Bethlehem, Pennsylvania 18015, United States.|College of Public Health, University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Jonas
authors.initials: J
authors.lastname: Baltrusaitis
authors.affiliation: Department of Chemistry, Stony Brook University , Stony Brook, New York 11794, United States.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Patterson
authors.affiliation: Department of Civil and Environmental Engineering, University of Iowa , 4105 Seamans Center for the Engineering Arts and Sciences, Iowa City, Iowa 52242, United States.
authors.forename: Meghan
authors.initials: M
authors.lastname: O'Connor
authors.affiliation: Department of Civil and Environmental Engineering, University of Iowa , 4105 Seamans Center for the Engineering Arts and Sciences, Iowa City, Iowa 52242, United States.
authors.forename: Shen
authors.initials: S
authors.lastname: Qu
authors.affiliation: Interdisciplinary Arts and Sciences, University of Washington , Tacoma, Tacoma Washington 98402, United States.|Civil and Environmental Engineering, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Kolodziej
authors.affiliation: Department of Civil and Environmental Engineering, University of Iowa , 4105 Seamans Center for the Engineering Arts and Sciences, Iowa City, Iowa 52242, United States.|Department of Chemical and Biochemical Engineering, University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: David M
authors.initials: DM
authors.lastname: Cwiertny
mesh_terms: D010782:Photolysis; D014204:Trenbolone Acetate; D014867:Water / Q000737:chemistry; D014874:Water Pollutants, Chemical
chemical_list: D014874:Water Pollutants, Chemical; D014867:Water; D014204:Trenbolone Acetate