ABSTRACT
Several neurodegenerative diseases have a common pathophysiology where selective damage to neurons results from the accumulation of amyloid oligomer proteins formed via fibrilization. Considering that the formation of amyloid oligomers leads to cytotoxicity, the development of chemical compounds that are able to effectively cross the blood-brain barrier (BBB) and inhibit this conversion to oligomers and/or fibrils is essential for neurodegenerative disease therapy. We previously reported that pyrroloquinoline quinone (PQQ) prevented aggregation and fibrillation of α-synuclein, amyloid ß1-42 (Aß1-42), and mouse prion protein. To develop a novel drug against neurodegenerative diseases based on PQQ, it is necessary to improve the insufficient BBB permeability of PQQ. Here, we show that an esterified compound of PQQ, PQQ-trimethylester (PQQ-TME), has twice the BBB permeability than PQQ in vitro. Moreover, PQQ-TME exhibited greater inhibitory activity against fibrillation of α-synuclein, Aß1-42, and prion protein. These results indicated that esterification of PQQ could be a useful approach in developing a novel PQQ-based amyloid inhibitor.
Subject(s)
Amyloid beta-Peptides/drug effects , Amyloid/drug effects , Amyloidogenic Proteins/drug effects , Blood-Brain Barrier/metabolism , Neurons/drug effects , PQQ Cofactor/analogs & derivatives , Peptide Fragments/drug effects , Prion Proteins/drug effects , Protein Aggregation, Pathological/metabolism , alpha-Synuclein/drug effects , Amyloid beta-Peptides/metabolism , Animals , Cell Line, Tumor , Cell Survival/drug effects , Esterification , Esters/chemical synthesis , Esters/pharmacology , Humans , Mice , Neurons/metabolism , PQQ Cofactor/chemical synthesis , PQQ Cofactor/pharmacology , Peptide Fragments/metabolism , Permeability , Prion Proteins/metabolism , alpha-Synuclein/metabolismABSTRACT
Catalytic enantio- and diastereoselective nitroaldol reactions were explored by using designed guanidine-thiourea bifunctional organocatalysts under mild and operationally simple biphasic conditions. These catalytic asymmetric reactions have a broad substrate generality with respect to the variety of aldehydes and nitroalkanes. Based on this catalytic nitroaldol process, straightforward syntheses of cytoxazone and 4-epi-cytoxazone were achieved. These catalytic nitroaldol reactions require KI as an additive for highly asymmetric induction; it operates by inhibiting the retro mode of the reaction. On the basis of studies of structure and catalytic-activity relationships, a plausible guanidine-thiourea cooperative mechanism and a transition state of the catalytic reactions are proposed. Drastic substituent effects on the catalytic properties of this catalyst may lead to the development of new chiral surfactants.
