title: Identification of 5-Methoxyflavone as a Novel DNA Polymerase-Beta Inhibitor and Neuroprotective Agent against Beta-Amyloid Toxicity.
abstract: Cell-cycle reactivation is a core feature of degenerating neurons in Alzheimer's disease (AD) and Parkinson's disease (PD). A variety of stressors, including β-amyloid (Aβ) in the case of AD, can force neurons to leave quiescence and to initiate an ectopic DNA replication process, leading to neuronal death rather than division. As the primary polymerase (pol) involved in neuronal DNA replication, DNA pol-β contributes to neuronal death, and DNA pol-β inhibitors may prove to be effective neuroprotective agents. Currently, specific and highly active DNA pol-β inhibitors are lacking. Nine putative DNA pol-β inhibitors were identified in silico by querying the ZINC database, containing more than 35 million purchasable compounds. Following pharmacological evaluation, only 5-methoxyflavone (1) was validated as an inhibitor of DNA pol-β activity. Cultured primary neurons are a useful model to investigate the neuroprotective effects of potential DNA pol-β inhibitors, since these neurons undergo DNA replication and death when treated with Aβ. Consistent with the inhibition of DNA pol-β, 5-methoxyflavone (1) reduced the number of S-phase neurons and the ensuing apoptotic death triggered by Aβ. 5-Methoxyflavone (1) is the first flavonoid compound able to halt neurodegeneration via a definite molecular mechanism rather than through general antioxidant and anti-inflammatory properties.
authors.forename: Sara
authors.initials: S
authors.lastname: Merlo
authors.forename: Livia
authors.initials: L
authors.lastname: Basile
authors.affiliation: Institute of Biostructure and Bioimaging, National Research Council (CNR) , Catania, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Giuffrida
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Sortino
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guccione
authors.affiliation: Institute of Biostructure and Bioimaging, National Research Council (CNR) , Catania, Italy.
authors.forename: Agata
authors.initials: A
authors.lastname: Copani
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors*; D004261:DNA Replication / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010300:Parkinson Disease / Q000473:pathology
chemical_list: C000605748:5-methoxyflavone; D004791:Enzyme Inhibitors; D047309:Flavones; D018696:Neuroprotective Agents; D019951:DNA Polymerase beta