title: Multitargeted drug development: Discovery and profiling of dihydroxy substituted 1-aza-9-oxafluorenes as lead compounds targeting Alzheimer disease relevant kinases.
abstract: Alzheimer disease (AD) turned out to be a multifactorial process leading to neuronal decay. So far merely single target structures which attribute to the AD progression have been considered to develop specific drugs. However, such drug developments have been disappointing in clinical stages. Multitargeting of more than one target structure determines recent studies of developing novel lead compounds. Protein kinases have been identified to contribute to the neuronal decay with CDK1, GSK-3β and CDK5/p25 being involved in a pathological tau protein hyperphosphorylation. We discovered novel lead structures of the dihydroxy-1-aza-9-oxafluorene type with nanomolar activities against CDK1, GSK-3β and CDK5/p25. Structure-activity relationships (SAR) of the protein kinase inhibition are discussed within our first compound series. One nanomolar active compound profiled as selective protein kinase inhibitor. Bioanalysis of a harmless cellular toxicity and of the inhibition of tau protein phosphorylation qualifies the compound for further studies.
authors.affiliation: Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Tell
authors.forename: Max
authors.initials: M
authors.lastname: Holzer
authors.forename: Lydia
authors.initials: L
authors.lastname: Herrmann
authors.forename: Kazem Ahmed
authors.initials: KA
authors.lastname: Mahmoud
authors.forename: Christoph
authors.initials: C
authors.lastname: Schächtele
authors.forename: Frank
authors.initials: F
authors.lastname: Totzke
authors.forename: Andreas
authors.initials: A
authors.lastname: Hilgeroth
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D001372:Aza Compounds / Q000737:chemistry*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005449:Fluorenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000378:metabolism
chemical_list: D001372:Aza Compounds; D005449:Fluorenes; D047428:Protein Kinase Inhibitors; D016875:tau Proteins; D011494:Protein Kinases; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D016203:CDC2 Protein Kinase; D038362:Glycogen Synthase Kinase 3