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C-H Bond dissociation energies for a unique selection of tertiary amines that are known substrates or inhibitors of monoamine oxidase have been calculated using density functional theory. These amines are unusual because they are the only tertiary amines that exhibit MAO substrate or inhibitor behavior. The unique structural feature common to these specific compounds is an sp3-hybridized CH2 moiety, which is -both to nitrogen and an C=C or C≡C. The stabilization afforded the resulting radicals by extended delocalization dramatically lowers both the C-H bond strength of the substrate (R-H → R• + H•) and pKa of the corresponding radical cation (RH•+ → R• + H+). This interplay of structure and thermodynamics may provide the driving force for an electron transfer mechanism for MAO catalysis and inhibition.
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Reaction of O 2 with α-Aminoalkyl Radicals Derived from Tetrahydropyridines
Tetrahydropyridines, such as the Parkinsonian-symptom-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its derivatives are unique in that they are the only known tertiary amines that are monoamine oxidase (MAO) substrates or inhibitors. These compounds all possess an exceptionally weak C-H bond at C-6, which is alpha both to a nitrogen lone pair and a C=C. Radicals (R•) derived from hydrogen abstraction at this position are exceptionally stable. Similar to other -aminoalkyl radicals, these radicals react with oxygen at a nearly diffusion-controlled rate and are readily oxidized. Evidence suggests that while the initial product of this reaction is likely a peroxyl radical resulting from radical trapping (ROO•), a dihydropyridinium species (DHP+) is produced through what can be described as an overall inner-sphere electron transfer process. These results imply another role for O2 in the MAO catalytic cycle. In addition to regenerating the flavin moiety in MAO, O2 may also be directly involved in oxidizing the substrate radical.
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- Award ID(s):
- 2106188
- PAR ID:
- 10641655
- Publisher / Repository:
- American Chemical Society
- Date Published:
- Journal Name:
- The Journal of Physical Chemistry A
- Volume:
- 129
- Issue:
- 24
- ISSN:
- 1089-5639
- Page Range / eLocation ID:
- 5337 to 5342
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Results pertaining to the mechanism of the oxidation of the tertiary amine 1‐methyl‐4‐(1‐methyl‐1‐H‐pyrrol‐2‐yl)‐1,2,3,6‐tetrahydropyridine (MMTP, a close analog of the Parkinsonism inducing compound MPTP) by 3‐methyllumiflavin (3MLF), a chemical model for the FAD cofactor of monoamine oxidase, are reported. MMTP and related compounds are among the few tertiary amines that are monoamine oxidase B (MAO−B) substrates. The MMTP/3MLF reaction is catalytic in the presence of O2and the results under anaerobic conditions strongly suggest the involvement of radical intermediates, consistent with a single electron transfer mechanism. These observations support a new hypothesis to explain the MAO‐catalyzed oxidations of amines. In general, electron transfer is thermodynamically unfavorable, and as a result, most 1° and 2° amines react via one of the currently accepted polar pathways. Steric constraints prevent 3° amines from reacting via a polar pathway. Those select 3° amines that are MAO substrates possess certain structural features (e. g., a C−H bond that is α‐ both to nitrogen and a C=C) that dramatically lower the pKaof the corresponding radical cation. Consequently, the thermodynamically unfavorable electron transfer equilibrium is driven towards products by an extremely favorable deprotonation step in the context of Le Chatelier's principle.more » « less
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1021/acs.jpca.5c02967
