New hydroxystilbenoid derivatives endowed with neuroprotective activity and devoid of interference with estrogen and aryl hydrocarbon receptor-mediated transcription.
We have synthesized a series of new (E) stilbenoid derivatives containing hydroxy groups at ring positions identical or similar to those of trans-resveratrol and bearing one or two bulky electron donating groups ortho to 4'-OH and we have evaluated their neuroprotective activity using glutamate-challenged HT22 hippocampal neurons to model oxidative stress-induced neuronal cell death. The most active derivatives, 5-{(E)-2-[3,5-bis(1-ethylpropyl)-4-hydroxyphenyl]ethenyl}-1,3-benzenediol (2), 5-[(E)-2-(3,5-di-tert-butyl-4-hydroxyphenylethenyl)]-1,3-benzenediol (4) and 5-{(1E,3E)-4-[3,5-bis(1-ethylpropyl)-4-hydroxyphenyl]-1,3-butadienyl}-1,3-benzenediol (6), had EC(50) values of 30, 45 and 12nM, respectively, and were ca. 100 to 400-fold more potent than resveratrol. Derivatives 2, 4 and 6 lacked cytotoxic activity against HT22 cells and estrogen receptor agonist or antagonist activity in estrogen response element-dependent gene expression and in estrogen-dependent proliferation of MCF-7 human breast cancer cells. In addition, they were incapable of interfering with aryl hydrocarbon receptor-mediated xenobiotic response element-dependent gene expression. Derivatives 2, 4 and 6 might assist in the development of lead candidates against oxidative stress-driven neurodegenerative diseases that will not increase endocrine cancer risk nor affect drug activation and detoxification mechanisms.
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 116 35 Athens, Greece.
Carolina
C
Villalonga-Barber
Aggeliki K
AK
Meligova
Xanthippi
X
Alexi
Barry R
BR
Steele
Constantinos E
CE
Kouzinos
Constantinos G
CG
Screttas
Efrosini S
ES
Katsanou
Maria
M
Micha-Screttas
Michael N
MN
Alexis
D009682:Magnetic Resonance Spectroscopy; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000502:physiology*
D018696:Neuroprotective Agents; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D013267:Stilbenes