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.

Chemical constituents from the ethyl acetate extract of the stems of Macaranga balansae Gagnep.

“…The NMR data are identical to those of reported trans-coniferyl aldehyde. [5] Compound 3 was isolated as a white solid, mp 280- . Analytical NMR and MS data indicated that the structure of 4 is stigmastane 3β,5α,6β-triol.…”

“…A phytochemical study of the ethyl acetate extract of the stems of M. balansae led to the isolation of six compounds including (-)-dehydroxycubebin (1), trans-coniferyl aldehyde (2), 3,3',4'-tri-O-methyl ellagic acid (3), stigmastane 3β,5α,6β-triol (4), 2,3dihydroxy-1-(4'-hydroxy-3'-methoxyphenyl) propan-1-one (5), and protocatechuic acid (6). Their chemical structures were elucidated by spectroscopic NMR and MS data.…”

“…However, the chemical composition of this plant has not been studied. The present paper describes the isolation and structure elucidation of six compounds including (-)-dehydroxycubebin (1), trans-coniferyl aldehyde (2), 3,3',4'-tri-O-methyl ellagic acid (3), stigmastane 3β,5α,6β-triol (4), 2,3dihydroxy-1-(4'-hydroxy-3'-methoxyphenyl)-propan-1-one (5), and protocatechuic acid (6) from ethyl acetate extract of M. balansea.…”

White Birch Trunk Extracts as a Source of Organic Compounds

“…Furthermore, 1,7‐bis‐(3,4‐dihydroxyphenyl)hept‐4‐ene‐3‐one ( i4 ) and 1,7‐bis(4‐hydroxyphenyl)‐hept‐4‐ene‐3‐one ( i11 ) were also identified in methanolic extracts from the barks of birch and alder species ,,,. Moreover, 1,7‐bis(4‐hydroxyphenyl)‐3‐hydroxyhept‐3‐ene ( i10 ) was described in the literature as well . Compounds i9 , i12 , i13 , i14 , i15 , and i16 could not be assigned to an exact chemical structure yet because various isomeric structures are present in these examples.…”

“…[12,14c,17,19] Moreover, 1,7-bis(4-hydroxyphenyl)-3hydroxyhept-3-ene (i10) was described in the literature as well. [18] Compounds i9, i12, i13, i14, i15, and i16 could not be assigned to an exact chemical structure yet because various isomeric structures are present in these examples.…”