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-<i>p</i>-coumarate (<b>pcm</b>) and methyl caffeate (<b>cm</b>) was previously found to yield potent antitumor metabolites. Here, we report the formation of potent...
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| Format: | Article |
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MDPI AG
2020-11-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/11/1537 |
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| author | Laura Fási Ahmed Dhahir Latif István Zupkó Sándor Lévai Miklós Dékány Zoltán Béni Árpád Könczöl György Tibor Balogh Attila Hunyadi |
| author_facet | Laura Fási Ahmed Dhahir Latif István Zupkó Sándor Lévai Miklós Dékány Zoltán Béni Árpád Könczöl György Tibor Balogh Attila Hunyadi |
| author_sort | Laura Fási |
| collection | DOAJ |
| description | Hydroxycinnamic acids represent a versatile group of dietary plant antioxidants. Oxidation of methyl-<i>p</i>-coumarate (<b>pcm</b>) and methyl caffeate (<b>cm</b>) was previously found to yield potent antitumor metabolites. Here, we report the formation of potentially bioactive products of <b>pcm</b> and <b>cm</b> 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 <b>pcm</b> with ONOO¯ produced two fragments, an o-nitrophenol derivative, and a new chlorinated compound. Bioactivity-guided isolation from the reaction mixture of <b>cm</b> 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 <b>cm</b> and ONOO¯. Our results demonstrate the ROS/RNS dependent formation of chemically stable metabolites, including a potent antitumor agent (<b>5</b>), 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. |
| first_indexed | 2024-03-10T14:56:14Z |
| format | Article |
| id | doaj.art-cdaff3c3912c469698fab3c71b09989d |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T14:56:14Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-cdaff3c3912c469698fab3c71b09989d2023-11-20T20:34:34ZengMDPI AGBiomolecules2218-273X2020-11-011011153710.3390/biom10111537AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor MetaboliteLaura Fási0Ahmed Dhahir Latif1István Zupkó2Sándor Lévai3Miklós Dékány4Zoltán Béni5Árpád Könczöl6György Tibor Balogh7Attila Hunyadi8Institute of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, Eötvös str. 6, H-6720 Szeged, HungaryInstitute of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, Eötvös str. 6, H-6720 Szeged, HungaryDepartment of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös str. 6, H-6720 Szeged, HungaryDepartment of Chemistry, Gedeon Richter Plc., Gyömrői u. 19-21, H-1103 Budapest, HungaryDepartment of Chemistry, Gedeon Richter Plc., Gyömrői u. 19-21, H-1103 Budapest, HungaryDepartment of Chemistry, Gedeon Richter Plc., Gyömrői u. 19-21, H-1103 Budapest, HungaryDepartment of Chemistry, Gedeon Richter Plc., Gyömrői u. 19-21, H-1103 Budapest, HungaryDepartment of Chemistry, Gedeon Richter Plc., Gyömrői u. 19-21, H-1103 Budapest, HungaryInstitute of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, Eötvös str. 6, H-6720 Szeged, HungaryHydroxycinnamic acids represent a versatile group of dietary plant antioxidants. Oxidation of methyl-<i>p</i>-coumarate (<b>pcm</b>) and methyl caffeate (<b>cm</b>) was previously found to yield potent antitumor metabolites. Here, we report the formation of potentially bioactive products of <b>pcm</b> and <b>cm</b> 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 <b>pcm</b> with ONOO¯ produced two fragments, an o-nitrophenol derivative, and a new chlorinated compound. Bioactivity-guided isolation from the reaction mixture of <b>cm</b> 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 <b>cm</b> and ONOO¯. Our results demonstrate the ROS/RNS dependent formation of chemically stable metabolites, including a potent antitumor agent (<b>5</b>), 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.https://www.mdpi.com/2218-273X/10/11/1537antioxidanthydroxycinnamatemethyl <i>p</i>-coumaratemethyl caffeatelignanreactive oxygen and nitrogen species |
| spellingShingle | Laura Fási Ahmed Dhahir Latif István Zupkó Sándor Lévai Miklós Dékány Zoltán Béni Árpád Könczöl György Tibor Balogh Attila Hunyadi AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor Metabolite Biomolecules antioxidant hydroxycinnamate methyl <i>p</i>-coumarate methyl caffeate lignan reactive oxygen and nitrogen species |
| 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 | antioxidant hydroxycinnamate methyl <i>p</i>-coumarate methyl caffeate lignan reactive oxygen and nitrogen species |
| url | https://www.mdpi.com/2218-273X/10/11/1537 |
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