title: Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer's disease.
abstract: 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.
authors: Department of Pharmacognosy, Pharacology, Chemistry and Biochemistry, School of Pharmacy, University of Mississippi, Mississippi 38677, USA.
authors: Mark
authors: M
authors: Hamann
authors: Diana
authors: D
authors: Alonso
authors: Ester
authors: E
authors: Martín-Aparicio
authors: Ana
authors: A
authors: Fuertes
authors: M José
authors: MJ
authors: Pérez-Puerto
authors: Ana
authors: A
authors: Castro
authors: Susana
authors: S
authors: Morales
authors: María Luisa
authors: ML
authors: Navarro
authors: María
authors: M
authors: Del Monte-Millán
authors: Miguel
authors: M
authors: Medina
authors: Hari
authors: H
authors: Pennaka
authors: Akula
authors: A
authors: Balaiah
authors: Jiangnan
authors: J
authors: Peng
authors: Jennifer
authors: J
authors: Cook
authors: Subagus
authors: S
authors: Wahyuono
authors: Ana
authors: A
authors: Martínez
mesh_terms: 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
chemical_list: D000470:Alkaloids; D002227:Carbazoles; C078290:manzamine A; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3