title: Syntheses of tricyclic pyrones and pyridinones and protection of Abeta-peptide induced MC65 neuronal cell death.
abstract: The SbetaC gene is conditionally expressed a 99-residue carboxy terminal fragment, C99, of amyloid precursor protein in MC65 cells and causes cell death. Consequently, MC65 cell line was used to identify inhibitors of toxicity related to intracellular amyloid beta (Abeta) oligomers. Compounds that reduce the level of Abeta peptides, prevent Abeta aggregation, or eliminate existing Abeta aggregates may be used in the treatment of Alzheimer's disease (AD). Previously, we found that a tricyclic pyrone (TP) molecule, compound 1, prevents MC65 cell death and inhibits Abeta aggregation. Hence various TPs containing heterocycle at C7 side chain and a nitrogen at position 2 or 5 were synthesized and their MC65 cell protective activities evaluated. TPs containing N3'-adenine moiety such as compounds 1 and 11 are most active with EC(50) values of 0.31 and 0.35 microM, respectively. EC(50) values of tricyclic N5-analog, pyranoisoquinolinone 13, and N2-analog, pyranopyridinone 20, are 2.49 and 1.25 microM, respectively, despite the lack of adenine moiety. Further investigation of tricyclic N2- and N5-analogs is warranted.
authors.affiliation: Department of Chemistry, Kansas State University, Manhattan, KS 66506-3701, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Rana
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Hong
authors.forename: Lydia
authors.initials: L
authors.lastname: Barrigan
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.forename: Duy H
authors.initials: DH
authors.lastname: Hua
mesh_terms: D000225:Adenine / Q000737:chemistry; D000544:Alzheimer Disease / Q000188:drug therapy; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D016923:Cell Death; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D008956:Models, Chemical; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009584:Nitrogen / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011728:Pyridones / Q000737:chemistry; D011753:Pyrones / Q000737:chemistry
chemical_list: D016564:Amyloid beta-Protein Precursor; D010455:Peptides; D011728:Pyridones; D011753:Pyrones; D000225:Adenine; D009584:Nitrogen