Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer's disease.
Manzamine A and related derivatives isolated from a common Indonesian sponge, Acanthostrongylophora, have been identified as a new class of GSK-3beta inhibitors. The semisynthesis of new analogues and the first structure-activity relationship studies with GSK-3beta are also reported. Moreover, manzamine A proved to be effective in decreasing tau hyperphosphorylation in human neuroblastoma cell lines, a demonstration of its ability to enter cells and interfere with tau pathology. Inhibition studies of manzamine A against a selected panel of five different kinases related to GSK-3beta, specifically CDK-1, PKA, CDK-5, MAPK, and GSK-3alpha, show the specific inhibition of manzamine A on GSK-3beta and CDK-5, the two kinases involved in tau pathological hyperphosphorylation. These results suggest that manzamine A constitutes a promising scaffold from which more potent and selective GSK-3 inhibitors could be designed as potential therapeutic agents for Alzheimer's disease.
Hamann
Mark
M
Department of Pharmacognosy, Pharacology, Chemistry and Biochemistry, School of Pharmacy, University of Mississippi, Mississippi 38677, USA.
Alonso
Diana
D
Martín-Aparicio
Ester
E
Fuertes
Ana
A
Pérez-Puerto
M José
MJ
Castro
Ana
A
Morales
Susana
S
Navarro
María Luisa
ML
Del Monte-Millán
María
M
Medina
Miguel
M
Pennaka
Hari
H
Balaiah
Akula
A
Peng
Jiangnan
J
Cook
Jennifer
J
Wahyuono
Subagus
S
Martínez
Ana
A
D000470:Alkaloids / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D002227:Carbazoles / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007214:Indonesia; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000470:Alkaloids; D002227:Carbazoles; C078290:manzamine A; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3