IN-VITRO METABOLISM OF 1,3-DIOXANE, 1,3-OXATHIOLANE, AND 1,3-DITHIANEDERIVATIVES OF THEOPHYLLINE - A STRUCTURE-METABOLISM CORRELATION STUDY

Correlation between structure and metabolism was studied within a seri es of cyclic acetal and thioacetal theophylline derivatives. All the c ompounds showed marked regioselectivity in in vitro metabolism, the me tabolites arising only from 7-cycloalkyl side chain transformation. Th e 1,3-dioxane derivative, besides N-dealkylation to theophylline, unde rwent enzymatic ring cleavage, through the oxidation of the acetal car bon and subsequent rearrangement. Thus the acetal group was converted enzymatically to an ester. A similar transformation, catalyzed by cyto chrome 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 oxidativ e metabolism. The metabolites arise only from the oxidation of the sul fur atom, the major nucleophilic center in the molecule. No N-dealkyla tion to theophylline was observed. Enzymatic sulfoxidation proceeded d iastereoselectively 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 d etected in the incubations.