Fási, Laura and Di Meo, Florent and Kuo, Ching-Ying and Stojkovic Buric, Sonja and Martins, Ana and Kúsz, Norbert and Béni, Zoltán and Dékány, Miklós and Balogh, György Tibor and Pesic, Milica and Wang, Hui-Chun and Trouillas, Patrick and Hunyadi, Attila (2019) Antioxidant-inspired drug discovery: antitumor metabolite is formed in situ from a hydroxycinnamic acid derivative upon free radical scavenging. JOURNAL OF MEDICINAL CHEMISTRY, 62 (3). pp. 1657-1668. ISSN 0022-2623
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Abstract
Cancer cells generally possess higher levels of reactive oxygen species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p-coumaric acid methyl ester (pcm) revealed a new antitumor lead, graviquinone. Graviquinone bypassed ABCB1-mediated resistance, induced DNA damage in lung carcinoma cells but exerted DNA protective activity in normal keratinocytes, and modulated DNA damage response in MCF-7 cells. The cytotoxic effect of pcm in MCF-7 cells was potentiated under H2O2-induced oxidative stress, and the formation of graviquinone was confirmed by Fenton's reaction on pcm. In silico density functional theory calculations suggested graviquinone as a kinetic product of pcm-scavenging (OH)-O-center dot radicals. Our results demonstrate the pharmacological value of an in situ-formed, oxidative stress-related metabolite of an antioxidant. This might be of particular importance for designing new strategies for antioxidant-based drug discovery.
Item Type: | Article |
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Subjects: | Q Science / természettudomány > QR Microbiology / mikrobiológia |
SWORD Depositor: | MTMT SWORD |
Depositing User: | MTMT SWORD |
Date Deposited: | 21 Nov 2019 14:31 |
Last Modified: | 21 Nov 2019 14:31 |
URI: | http://real.mtak.hu/id/eprint/103509 |
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