The Bioorganic Chemistry of N-Allyl and N-Propargyl Substituents in Drug Interactions with Flavin-linked Oxidases

Abstract

Attention is focused on recent mechanistic proposals concerning the unique inhibitory properties of N-propargyl substituents toward flavin-linked oxidases. Model studies with sarcosine oxidase have revealed that the enzyme displays absolute substrate specificity. Unexpectedly however, substitution of the N-methyl group of the substrate by the N-allyl or N-propargyl functions led to a time-dependent irreversible inactivation of the enzyme. The rate of in-activation by these substrate analogs was markedly retarded by deuterium substitution in the methylene group of the allyl and propargyl functions. It is concluded, mainly on that basis, that N-allyl and N-propargyl glycine are inhibitory substrates for the enzyme, alkylating species being generated at the active site level of the enzyme. The implications of these findings in the mechanism of action of medicinally important drugs are briefly mentioned.