Reversible Photohydration of Trenbolone Acetate Metabolites: Mechanistic Understanding of Product-To-Parent Reversion Through Complementary Experimental and Theoretical Approaches
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.
Environmental Science & Technology
pre-print, post-print (with 12 month embargo)
Baltrusaitis, J.; Patterson, E.V.; O'Connor, M.; Qu, S.; Kolodziej, E.P.; and Cwiertny, D.M., "Reversible Photohydration of Trenbolone Acetate Metabolites: Mechanistic Understanding of Product-To-Parent Reversion Through Complementary Experimental and Theoretical Approaches" (2016). SIAS Faculty Publications. 577.
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