Formation and Reaction of the Quinone Methide from Reductive Cleavage of the Antitumor Drug Menogaril

Article abstract of DOI:10.1021/ja00188a050

Anaerobic reduction of menogaril (1), a semisynthetic antiumor drug in clinical trials, with d,l-bi(3,5,5-trimethyl-2-oxomorpholin-3-yl) (TM-3 dimer) in methanol gave 7-deoxynogarol (5) and stereoisomers of bi(7-deoxynogarol-7-yl) (6) and, in the presence of N-acetylcysteine, 7-(N-acetylcysteinyl)-7-deoxynogarol (10) via an observed quinone methide intermediate (8).In the presence of excess reducing agent, 5 was formed relatively rapidly as the major product in its hydroquinone state.The rate-controlling step, tautomerization of the quinone methide, was autocatalyzed; the product, the hydroquinone of 5, catalyzed the reaction.In fact, several anthracycline-derived hydroquinones were effective catalysts.Uncatalyzed tautomerization of the quinone methide yielded little if any 5, in contrast with facile unimolecular formation of 7-deoxyaglycons from reduction of other anthracyclines.In the absence or presence of excess reducing agent, the rate of formation of 6 or formation of 6 in its bishydroquinone state, respectively, was second order in quinone methide concentration and relatively slow.The rate constants for the autocatalyzed tautomerization and the dimerization of the quinone methide are 27 +/- 2 and 11+/-1 M^-1s^-1, respectively.Reduction of menogaril in aqueous medium gave predominantly 7-deoxynogarol (5) relatively rapidly with excess reducing agent and a mixture of 5 and the aglycon dimer 6 slowly with substoichiometric amounts of reducing agent.Under both sets of conditions, the quinone methide transient was not observed.Reduction in aqueos medium with 0.3 equiv of reducing agent in the presence of N-acetylcysteine gave high yields of adduct 10, suggesting a relatively longlifetime for the unobservable quinone methide transient even in aqueous medium in the absence of hydroquinones and reactive nucleophiles.A possible in vivo consequence of the relatively slow uncatalyzed tautomerization of the quinone methide is efficient nucleophilic trapping.