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AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor Metabolite

Hydroxycinnamic acids represent a versatile group of dietary plant antioxidants. Oxidation of methyl-p-coumarate (pcm) and methyl caffeate (cm) was previously found to yield potent antitumor metabolites. Here, we report the formation of potentially bioactive products of pcm and cm oxidized with pero...

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Autores principales: Fási, Laura, Latif, Ahmed Dhahir, Zupkó, István, Lévai, Sándor, Dékány, Miklós, Béni, Zoltán, Könczöl, Árpád, Balogh, György Tibor, Hunyadi, Attila
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697082/
https://www.ncbi.nlm.nih.gov/pubmed/33187226
http://dx.doi.org/10.3390/biom10111537
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author Fási, Laura
Latif, Ahmed Dhahir
Zupkó, István
Lévai, Sándor
Dékány, Miklós
Béni, Zoltán
Könczöl, Árpád
Balogh, György Tibor
Hunyadi, Attila
author_facet Fási, Laura
Latif, Ahmed Dhahir
Zupkó, István
Lévai, Sándor
Dékány, Miklós
Béni, Zoltán
Könczöl, Árpád
Balogh, György Tibor
Hunyadi, Attila
author_sort Fási, Laura
collection PubMed
description Hydroxycinnamic acids represent a versatile group of dietary plant antioxidants. Oxidation of methyl-p-coumarate (pcm) and methyl caffeate (cm) was previously found to yield potent antitumor metabolites. Here, we report the formation of potentially bioactive products of pcm and cm oxidized with peroxynitrite (ONOO¯), a biologically relevant reactive nitrogen species (RNS), or with α,α′-azodiisobutyramidine dihydrochloride (AAPH) as a chemical model for reactive oxygen species (ROS). A continuous flow system was developed to achieve reproducible in situ ONOO¯ formation. Reaction mixtures were tested for their cytotoxic effect on HeLa, SiHa, MCF-7 and MDA-MB-231 cells. The reaction of pcm with ONOO¯ produced two fragments, an o-nitrophenol derivative, and a new chlorinated compound. Bioactivity-guided isolation from the reaction mixture of cm with AAPH produced two dimerization products, including a dihydrobenzofuran lignan that exerted strong antitumor activity in vitro, and has potent in vivo antimetastatic activity which was previously reported. This compound was also detected from the reaction between cm and ONOO¯. Our results demonstrate the ROS/RNS dependent formation of chemically stable metabolites, including a potent antitumor agent (5), from hydroxycinnamic acids. This suggests that diversity-oriented synthesis using ROS/RNS to obtain oxidized antioxidant metabolite mixtures may serve as a valid natural product-based drug discovery strategy.
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spelling pubmed-76970822020-11-29 AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor Metabolite Fási, Laura Latif, Ahmed Dhahir Zupkó, István Lévai, Sándor Dékány, Miklós Béni, Zoltán Könczöl, Árpád Balogh, György Tibor Hunyadi, Attila Biomolecules Article Hydroxycinnamic acids represent a versatile group of dietary plant antioxidants. Oxidation of methyl-p-coumarate (pcm) and methyl caffeate (cm) was previously found to yield potent antitumor metabolites. Here, we report the formation of potentially bioactive products of pcm and cm oxidized with peroxynitrite (ONOO¯), a biologically relevant reactive nitrogen species (RNS), or with α,α′-azodiisobutyramidine dihydrochloride (AAPH) as a chemical model for reactive oxygen species (ROS). A continuous flow system was developed to achieve reproducible in situ ONOO¯ formation. Reaction mixtures were tested for their cytotoxic effect on HeLa, SiHa, MCF-7 and MDA-MB-231 cells. The reaction of pcm with ONOO¯ produced two fragments, an o-nitrophenol derivative, and a new chlorinated compound. Bioactivity-guided isolation from the reaction mixture of cm with AAPH produced two dimerization products, including a dihydrobenzofuran lignan that exerted strong antitumor activity in vitro, and has potent in vivo antimetastatic activity which was previously reported. This compound was also detected from the reaction between cm and ONOO¯. Our results demonstrate the ROS/RNS dependent formation of chemically stable metabolites, including a potent antitumor agent (5), from hydroxycinnamic acids. This suggests that diversity-oriented synthesis using ROS/RNS to obtain oxidized antioxidant metabolite mixtures may serve as a valid natural product-based drug discovery strategy. MDPI 2020-11-11 /pmc/articles/PMC7697082/ /pubmed/33187226 http://dx.doi.org/10.3390/biom10111537 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fási, Laura
Latif, Ahmed Dhahir
Zupkó, István
Lévai, Sándor
Dékány, Miklós
Béni, Zoltán
Könczöl, Árpád
Balogh, György Tibor
Hunyadi, Attila
AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor Metabolite
title AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor Metabolite
title_full AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor Metabolite
title_fullStr AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor Metabolite
title_full_unstemmed AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor Metabolite
title_short AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor Metabolite
title_sort aaph or peroxynitrite-induced biorelevant oxidation of methyl caffeate yields a potent antitumor metabolite
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697082/
https://www.ncbi.nlm.nih.gov/pubmed/33187226
http://dx.doi.org/10.3390/biom10111537
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