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

Sandeep Rana, Hyun Seok Hong, Lydia Barrigan, Lee-Way Jin, Duy H. Hua

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The SβC 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 β (Aβ) oligomers. Compounds that reduce the level of Aβ peptides, prevent Aβ aggregation, or eliminate existing Aβ 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 Aβ 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 μM, respectively. EC50 values of tricyclic N5-analog, pyranoisoquinolinone 13, and N2-analog, pyranopyridinone 20, are 2.49 and 1.25 μM, respectively, despite the lack of adenine moiety. Further investigation of tricyclic N2- and N5-analogs is warranted.

Original languageEnglish (US)
Pages (from-to)670-674
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number3
DOIs
StatePublished - Feb 1 2009

Keywords

  • Alzheimer's disease
  • Protection of MC65 cell death
  • Tricyclic pyrones

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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