TY - JOUR
T1 - Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine
AU - Luo, Weiming
AU - Yu, Qian Sheng
AU - Zhan, Ming
AU - Parrish, Damon
AU - Deschamps, Jeffrey R.
AU - Kulkarni, Santosh S.
AU - Holloway, Harold W.
AU - Alley, George M.
AU - Lahiri, Debomoy K.
AU - Brossi, Arnold
AU - Greig, Nigel H.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/2/24
Y1 - 2005/2/24
N2 - Reductive cyclization of 5-hydroxy-3-methyl-3- methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3, 3a,8a-tatrahydrofuro[2,3-6]benzofuran (5) and the rearrangement product 7-hydroxy-4,5-dihydro-2,5-methano-1,3-benzodioxepine (6). Reaction of compounds 5 and 6 with different isocyanates provided two series novel carbamates (7-12) whose structures were confirmed by X-ray crystallography. These were assessed for anticholinesterase action against freshly prepared human enzyme and proved to be potent inhibitors of either acetyl- (AChE) or butyrylcholinesterase (BChE) with specific compounds exhibiting remarkable selectivity. Because the two series of carbamates (7-12) differ in their phenolic moieties, their respective potency and selectivity for AChE versus BChE was governed by their N-substituted groups. This same characteristic was also present in a series of physovenine analogues (1,13,15,17) and physostigmine analogues (2,14,16,18). These structure-activity relations proved valuable in elucidating the mechanisms underpinning the interaction between carbamate-based cholinesterase inhibitors and their enzyme target. In addition, because physostigmine analogues have demonstrated activity in lowering the Alzheimer's disease protein, amyloid precursor protein (APP), examples of the two new series of carbamates were characterized in culture assays of quantifying cell viability and synthesis of APP.
AB - Reductive cyclization of 5-hydroxy-3-methyl-3- methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3, 3a,8a-tatrahydrofuro[2,3-6]benzofuran (5) and the rearrangement product 7-hydroxy-4,5-dihydro-2,5-methano-1,3-benzodioxepine (6). Reaction of compounds 5 and 6 with different isocyanates provided two series novel carbamates (7-12) whose structures were confirmed by X-ray crystallography. These were assessed for anticholinesterase action against freshly prepared human enzyme and proved to be potent inhibitors of either acetyl- (AChE) or butyrylcholinesterase (BChE) with specific compounds exhibiting remarkable selectivity. Because the two series of carbamates (7-12) differ in their phenolic moieties, their respective potency and selectivity for AChE versus BChE was governed by their N-substituted groups. This same characteristic was also present in a series of physovenine analogues (1,13,15,17) and physostigmine analogues (2,14,16,18). These structure-activity relations proved valuable in elucidating the mechanisms underpinning the interaction between carbamate-based cholinesterase inhibitors and their enzyme target. In addition, because physostigmine analogues have demonstrated activity in lowering the Alzheimer's disease protein, amyloid precursor protein (APP), examples of the two new series of carbamates were characterized in culture assays of quantifying cell viability and synthesis of APP.
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U2 - 10.1021/jm049309+
DO - 10.1021/jm049309+
M3 - Article
C2 - 15715468
AN - SCOPUS:13944250571
SN - 0022-2623
VL - 48
SP - 986
EP - 994
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -