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New hydroxystilbenoid derivatives endowed with neuroprotective activity and devoid of interference with estrogen and aryl hydrocarbon receptor-mediated transcription

journal contribution
posted on 2023-06-08, 21:08 authored by Carolina Villalonga-Barber, Aggeliki K Meligova, Xanthippi Alexi, Barry R Steele, Constantinos E Kouzinos, Constantinos G Screttas, Efrosini S Katsanou, Maria Micha-Screttas, Michael N Alexis
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 EC50 values of 30, 45 and 12 nM, 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.

History

Publication status

  • Published

Journal

Bioorganic and Medicinal Chemistry

ISSN

0968-0896

Publisher

Elsevier

Issue

1

Volume

19

Page range

339-351

Department affiliated with

  • Chemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2015-06-16

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