ABSTRACT
Starting from quinuclidinyl oxime 1 identified by preliminary screening, a series of azacycles-containing oxime derivatives was synthesized. Their mPTP blocking activities were evaluated by a JC-1 assay, measuring the change of mitochondrial membrane potential. The inhibitory activity of nine compounds against amyloid beta-induced mPTP opening was comparable or even superior to that of piracetam. Among them, 12d effectively maintained mitochondrial function and cell viabilities on the ATP assay, the MTT assay, and the ROS assay. In addition, it exhibited favorable in vitro stability and pharmacokinetic characteristics, which hold a promise for further development of AD therapeutics.
Subject(s)
Amyloid beta-Peptides/pharmacology , Mitochondria/drug effects , Oximes/pharmacology , Animals , Cells, Cultured , Humans , Male , Mice , Mice, Inbred ICR , Mitochondria/metabolism , Mitochondrial Membranes/drug effects , Molecular Structure , Oximes/chemical synthesis , Oximes/chemistry , Rats , Rats, Sprague-DawleyABSTRACT
An efficient synthesis of 3,4-dimethylidene oxacycles including oxolanes and oxepanes through Prins-type cyclization of hydroxy(allenylmethyl)silanes is described. We have shown that 2-substituted tetrahydrofuran derivatives could be produced by using this strategy although the 5-endo-trig cyclization mode is stereoelectronically disfavored. We also applied our method to the stereoselective synthesis of 2,7-cis-3,4-dimethylidene oxepanes, which were used for constructing more complex ring systems, such as polyether bicycles or tricycles.
