Isolation and characterization of N98-1272 A, B and C, selective acetylcholinesterase inhibitors from metabolites of an actinomycete strain.
A high throughput screening was carried out in order to search for inhibitors of acetylcholinesterase (AChE) from microorganism metabolites. An actinomycete strain was found to produce active compounds named N98-1272 A, B and C with IC50 of 15.0, 11.5, 12.5 microM, respectively. Structural studies revealed that the three compounds are identical to the known antibiotics, Manumycin C, B and A. Kinetic analyses showed that N98-1272 C (Manumycin A) acted as a reversible noncompetitive inhibitor of acetylcholinesterase, with a Ki value of 7.2 microM. The cyclohexenone epoxide part of the structure plays a crucial role in the inhibitory activity against AChE. Compared with Tacrine, N98-1272 A, B, and C exhibit much better selectivity toward AChE over BuChE.
Zheng
Zhi-Hui
ZH
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing 100050, China.
Dong
Yue-Sheng
YS
Zhang
Hua
H
Lu
Xin-Hua
XH
Ren
Xiao
X
Zhao
Guiyu
G
He
Jian-Gong
JG
Si
Shu-Yi
SY
D000110:Acetylcholinesterase / Q000187:drug effects*; D039903:Actinobacteria / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase