In vitro metabolism of 1,3-dioxane, 1,3-oxathiolane, and 1,3-dithiane derivatives of theophylline: a structure-metabolism correlation study.
Correlation between structure and metabolism was studied within a series of cyclic acetal and thioacetal theophylline derivatives. All the compounds showed marked regioselectivity in in vitro metabolism, the metabolites arising only from 7-cycloalkyl side chain transformation. The 1,3-dioxane derivative, besides N-dealkylation to theophylline, underwent enzymatic ring cleavage, through the oxidation of the acetal carbon and subsequent rearrangement. Thus the acetal group was converted enzymatically to an ester. A similar transformation, catalyzed by cytochrome P450-dependent monooxygenases, was previously found for the 1,3-dioxolane ring of doxophylline. The cyclic thioacetal derivatives (i.e. 1,3-oxathiolane and 1,3-dithiane) were not cleaved during oxidative metabolism. The metabolites arise only from the oxidation of the sulfur atom, the major nucleophilic center in the molecule. No N-dealkylation to theophylline was observed. Enzymatic sulfoxidation proceeded diastereoselectively in both the 1,3-oxathiolane and 1,3-dithiane rings, the trans isomers being the major ones with a ratio trans: cis 75:25 and 60:40 respectively. The sulfoxides were stable to hydrolysis and were not further metabolized. Neither disulfoxides nor sulfones were detected in the incubations.[1]References
- In vitro metabolism of 1,3-dioxane, 1,3-oxathiolane, and 1,3-dithiane derivatives of theophylline: a structure-metabolism correlation study. Grosa, G., Rocco, F., Ceruti, M., Dosio, F., Brusa, P., Biglino, G. Farmaco (1993) [Pubmed]
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