Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction.
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.
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, South Korea.
Young Seub
YS
Kim
Sun Hwa
SH
Jung
Beoung-Geon
BG
Park
Min Kyung
MK
Ko
Hyun-Seo
HS
Jang
Kihang
K
Choi
Ja-Hyun
JH
Baik
Jiyoun
J
Lee
Jae Kyun
JK
Lee
Ae Nim
AN
Pae
Yong Seo
YS
Cho
Sun-Joon
SJ
Min
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D010091:Oximes