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Flavin Chemical Models for Monoamine Oxidase Inactivation by Cyclopropylamines, α-Silylamines, and Hydrazines
Models for the inactivation of the monoamine oxidase A and B, two closely related flavoenzymes, by cyclopropylamines, a-silylamines, and hydrazines have been investigated in order to gain insight into the possible chemical mechanisms for these processes. The activated (i.e. high reduction potential and electrophilicity) flavin, 3-methyl-5-ethyllumiflavinium perchlorate (S), was employed in this effort along with trans-2-phenylcyclopropylamine (l), a host of monosubstituted hydrazines (13-16), and a-(trimethylsilyl)benzylamine (9). Admixture of 5 with 1 (25 oC, MeCN) results in instantaneous formation of the stable and completely characterized flavin-amine adducts 6 (Ke = 2 x 104) derived by addition of the amine function in 1 to the 4a-position of 5. Reaction of the 4a-adduct 6 with cyclopropylamine 1 (85 oC, MeCN) cleanly (80%) produces the aldimine 7 formed by condensation of the initial product, trans-cinnamaldehyde and amine 5. These results demonstrate that 4a-adducts related to 6 are capable of undergoing cyclopropane ring opening reactions by polar pathways to produce electrophilic α,β-unsaturated carbonyl products. Consequently, ring opening reactions proposed for monoamine oxidase inactivation by primary and perhaps secondary cyclopropylamines can occur by polar routes and, thus, are not uniquely attributable to radical mechanistic pathways. In a similar manner, the flavinium salt 5 undergoes rapid reaction with the α-silylamine 9 to produce a stable 4a-adduct 10 (Ke = 7 x 104). Reaction of this adduct with 9 (45 oC, MeCN) leads to initial production of N-[(α-trimethylsilyl)benzyl]benzaldimine (12) which undergoes desilylation to produce N-benzylbenzaldimine (11) under these conditions. Also, 4a-adduct 10 is rapidly converted to aldimine 11 by reaction with TBAF at 25 oC in MeCN. These results show that 4a-adducts, generated from activated flavins and a-silylamines, participate in fragmentation processes leading to silylation of nucleophiles and production of carbonyl products. This polar mechanistic pathway models the known inactivation reactions of the MAOs by a-silylamines previously attributed to SET (radical) routes. Reaction of flavinium salt 5 with phenyl- or benzylhydrazine results in formation of 4a- phenyl or -benzyl flavin adducts. For example, admixture of 5 and PhNHNH2 in CHFN at 25 oC provides the characterizable 4a-phenyl and 4a-cyanomethyl flavins, 21 (28%) and 22 (55%), and benzene. Benzylhydrazine reacts similarly with 5 to produce only the 4a-benzyl adduct 23 (89%). Information about the mechanism for adduct formation in these reactions has come from studies with the hydrazine analogs, NH2NHCO2CH2Ph (15) and NH2OCH2Ph (16). These substances react rapidly with 5 in MeCN at 25 oC to cleanly produce stable 4a-hydrazine adducts, 17. The results suggest that 4a-alkylation or -arylation reactions of the activated flavin 5 with hydrazines probably occur via the intermediacy of 4a-hydrazine flavin adducts related to 17. Thus, a polar mechanistic model is also consistent with the known inactivation reactions of the MAOs with hydrazines which are also reported to generate 4a-flavin alkylated and arylated MAO derivatives.
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