A Biomimetic Study of the Behavior of N -Cyclopropyl-Based Single Electron Transfer Probes in the Context of Monoamine Oxidase-Catalyzed Oxidations

Monoamine oxidase-A and -B are important flavoenzymes involved in the oxidative metabolism of various biogenic amines. Mechanisms including polar/nucleophilic, hydride transfer, and single electron transfer (SET) have been proposed for the initial steps of the catalytic mechanism. The most compelling evidence for the latter comes from the observed inhibitory behavior of N-cyclopropyl compounds. Enzyme inactivation presumably occurs when the primary radical portion of the distonic radical cation, resulting from cyclopropyl ring opening, couples to the enzyme. Previously, we hypothesized that the unique substrate behavior of 1,4-disubstituted-1,2,3,6-tetrahydropyridinyl systems was attributable to certain structural features which activate the SET pathway. In the present work, the oxidation of several N-cyclopropyl derivatives of MPTP in a biomimetic system (3MLF/hν) is reported. Calculations suggest that the barrier to ring opening may not be as low as assumed, and experiments show the process is reversible. The results also suggest that the ring-opened (distonic) radical cation may disrupt the active site through radical coupling, hydrogen atom abstraction, or through reaction with O₂ that can lead to reactive oxygen species. Hydrolysis of an intermediate iminium moiety leads to the production of low molecular weight aldehydes, which may also provide a pathway for enzyme inactivation.