Models of folate coenzymes 16 : Chemical modelling of the thymidylate synthase reaction. Evidence for an “exocyclic methylene intermediate” analogue, which is reducible to a thymine derivative, in the reaction of 6-aminouracils with a 5,10-methylenetetrahydrofolate model

Abstract

Reactions of 6-amino-, 6-alkylamino- and 6-anilino-l,3-dimethyluracils ( 1a - e ) with 3,4-diphenyl-1-tosylimidazolidine ( 2 ), in the presence of acid, lead to the formation of products which are derived from an “exocyclic methylene intermediate” analogous to the one formed in the thymidylate synthase reaction. The intermediate has been identified by (a) spectral studies, (b) formation of adducts with dihydropyridine and dihydroquinonline derivatives and (c) its reduction to the corresponding thymine derivative. These results provide chemical precedence for the carbon transfer step of the thymidylate synthase reaction in a reaction between models of both the apoenzyme-substrate complex and the coenzyme 5,10-methylenetetrahydrofolate.