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Intermediates involved in serotonin oxidation catalyzed by Cu bound Aβ peptides.

ABSTRACT: The degradation of neurotransmitters is a hallmark feature of Alzheimer's disease (AD). Copper bound Aβ peptides, invoked to be involved in the pathology of AD, are found to catalyze the oxidation of serotonin (5-HT) by H₂O₂. A combination of EPR and resonance Raman spectroscopy reveals the formation of a Cu(ii)-OOH species and a dimeric, EPR silent, Cu₂O₂ bis-μ-oxo species under the reaction conditions. The Cu(ii)-OOH species, which can be selectively formed in the presence of excess H₂O₂, is the reactive intermediate responsible for 5-HT oxidation. H₂O₂ produced by the reaction of O₂ with reduced Cu(i)-Aβ species can also oxidize 5-HT. Both these pathways are physiologically relevant and may be involved in the observed decay of neurotransmitters as observed in AD patients.

SUBMITTER: Nath AK

PROVIDER: S-EPMC8179298 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Catalytic enantioselective boron-hydride additions to 1,3-enynes, which afford allenyl-B(pin) (pin = pinacolato) products, are disclosed. Transformations are promoted by a readily accessible bis-phosphine-Cu complex and involve commercially available HB(pin). The method is applicable to aryl- and alkyl-substituted 1,3-enynes. Trisubstituted allenyl-B(pin) products were generated in 52-80% yield and, in most cases, in >98:2 allenyl:propargyl and 92:8-99:1 enantiomeric ratio. Utility is highlighted through a highly diastereoselective addition to an aldehyde, and a stereospecific catalytic cross-coupling process that delivers an enantiomerically enriched allene with three carbon-based substituents. The following key mechanistic attributes are elucidated: (1) Spectroscopic and computational investigations indicate that low enantioselectivity can arise from loss of kinetic stereoselectivity, which, as suggested by experimental evidence, may occur by formation of a propargylic anion generated by heterolytic Cu-C cleavage. This is particularly a problem when trapping of the Cu-allenyl intermediate is slow, namely, when an electron deficient 1,3-enyne or a less reactive boron-hydride reagent (e.g., HB(dan) (dan = naphthalene-1,8-diaminato)) is used or under non-optimal conditions (e.g., lower boron-hydride concentration causing slower trapping). (2) With enynes that contain a sterically demanding o-aryl substituent considerable amounts of the propargyl-B(pin) isomer may be generated (25-96%) because a less sterically demanding transition state for Cu/B exchange becomes favorable. (3) The phosphine ligand can promote isomerization of the enantiomerically enriched allenyl-B(pin) product; accordingly, lower ligand loading might at times be optimal. (4) Catalytic cross-coupling with an enantiomerically enriched allenyl-B(pin) compound might proceed with high stereospecificity (e.g., phosphine-Pd-catalyzed cross-coupling) or lead to considerable racemization (e.g., phosphine-Cu-catalyzed allylic substitution).

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Intermediates involved in serotonin oxidation catalyzed by Cu bound Aβ peptides.

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