Syntheses of tricyclic pyrones and pyridinones and protection of Aβ-peptide induced MC65 neuronal cell death

The S beta C 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 (A beta) oligomers. Compounds that reduce the level of A beta peptides, prevent A beta aggregation, or eliminate existing A beta 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 A beta 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 EC50 values of 0.31 and 0.35 mu M, respectively. EC50 values of tricyclic N5-analog, pyranoisoquinolinone 13, and N2-analog, pyranopyridinone 20, are 2.49 and 1.25 mu M, respectively, despite the lack of adenine moiety. Further investigation of tricyclic N2- and N5-analogs is warranted. (c) 2008 Elsevier Ltd. All rights reserved.