Ka. Vanhouten et al., A NEW STRATEGY FOR THE DESIGN OF MONOAMINE-OXIDASE INACTIVATORS - EXPLORATORY STUDIES WITH TERTIARY ALLYLIC AND PROPARGYLIC AMINO-ALCOHOLS, Journal of the American Chemical Society, 120(24), 1998, pp. 5864-5872
A new strategy for the design of monoamine oxidase (MAO) inhibitors is
proposed. The strategy is based on the premise that tertiary-amine co
ntaining MAO-inactivators which operate by alkylation of active site n
ucleophiles are activated in sial by single electron transfer (SET) to
the MAO-flavin cofactor to form aminium cation radicals which undergo
secondary fragmentation reactions to produce reactive electrophiles,
The purpose of the current work was to assess the feasibility and appl
icability of this proposal for the design of new families of MAO-inact
ivacors. Based on the documented retro-aldol type fragmentation reacti
vity of beta-amino-alcohol cation radicals, tertiary beta-allylic and
-propargylic beta-amino-alcohols were expected to serve as precursors
of conjugated ketones in SET-promoted processes. Evidence supporting t
his hypothesis was gained from studies of model SET-photoreactions of
members of this amino-alcohol family with 3-methyl-lumiflavin (3MLF).
The efficient production of 4a- and 4a,5-flavin adducts in these excit
ed-state reactions demonstrates that aminium radicals. arising by SET-
oxidation of tertiary beta-allylic and -propargylic beta-amino-alcohol
s, fragment to generate alpha,beta-unsaturated ketones which react rap
idly with the simultaneously formed 3MLF-hydroflavin anion. The second
feature of the MAO-inactivator design strategy pathway was tested by
examining reactions of the MAOs with substances which contain electrop
hilic, conjungated enone and ynone moieties tethered to amine function
s to ensure delivery to the enzyme active sites. The covalent modifica
tion of active site cysteine thiol residues by the unsaturated ketone
groups in these substances was confirmed by demonstrating that they se
rve as active site-directed, time-dependent, nonredox based, inactivat
ors of MAO-A and MAO-B. In the key test of the feasibility of the new
MAO-inactivator design strategy, it was shown that selected tertiary b
eta-allylic and -propargylic beta-amino-alcohols undergo redox reactio
ns in the MAO-A active site which result in inactivation of the enzyme
via covalent modification of a single cysteine residue. The experimen
tal results which support the conclusions stated above are presented a
nd discussed in this paper.