title: Synthesis of natural and non-natural curcuminoids and their neuroprotective activity against glutamate-induced oxidative stress in HT-22 cells.
abstract: A strategy for the synthesis of natural and non-natural 5-deoxy-6,7-dihydrocurcuminoids (diarylheptanoids) was developed for the preparation of 14 compounds with varying aromatic substituent patterns and a different functionality in the aliphatic seven-carbon chain. The in vitro protective activity against glutamate-induced neuronal cell death was examined in the murine hippocampal cell line HT-22 to find structural motifs responsible for neuroprotective effects in vitro. Among the tested compounds the ferulic acid-like unit, present in the structures of (E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hept-1-en-3-one (5) and (E)-1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)hept-1-en-3-one (7), appeared to be an important feature for protection against glutamate-induced neurotoxicity. Both compounds demonstrated significant neuroprotective activity in a concentration range between 1 and 25 μM without showing toxic effects in a cytotoxicity assay with HT-22 cells. Furthermore, (E)-1,7-bis(3,4-dihydroxyphenyl)hept-1-en-3-one (9), exhibiting a caffeic acid-like structural motif, displayed a neuroprotective activity at a nontoxic concentration of 25 μM. In contrast, (1E,6E)-1,7-bis(3,4-dihydroxyphenyl)hepta-1,6-diene-3,5-dione (4, di-O-demethylcurcumin) showed mainly cytotoxic effects. A corresponding single-ring analogue that contains the ferulic acid-like unit as an enone was not active.
authors.affiliation: Institut für Pharmazie and ‡Institut für Organische Chemie, Universität Regensburg , Universitätsstraße 31, 93053 Regensburg, Germany.
authors.forename: Petr
authors.initials: P
authors.lastname: Jirásek
authors.forename: Sabine
authors.initials: S
authors.lastname: Amslinger
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003373:Coumaric Acids / Q000737:chemistry / Q000494:pharmacology; D036381:Diarylheptanoids / Q000138:chemical synthesis* / Q000494:pharmacology*; D005971:Glutamates; D018698:Glutamic Acid / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D003373:Coumaric Acids; D036381:Diarylheptanoids; D005971:Glutamates; D018696:Neuroprotective Agents; D018698:Glutamic Acid; C004999:ferulic acid