New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells
New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC<sub>50</sub&g...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/5/2243 |
| _version_ | 1797395445479112704 |
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| author | Eva Schaller Andi Ma Lisa Chiara Gosch Adrian Klefenz David Schaller Nils Goehringer Leonard Kaps Detlef Schuppan Andrea Volkamer Rainer Schobert Bernhard Biersack Bianca Nitzsche Michael Höpfner |
| author_facet | Eva Schaller Andi Ma Lisa Chiara Gosch Adrian Klefenz David Schaller Nils Goehringer Leonard Kaps Detlef Schuppan Andrea Volkamer Rainer Schobert Bernhard Biersack Bianca Nitzsche Michael Höpfner |
| author_sort | Eva Schaller |
| collection | DOAJ |
| description | New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC<sub>50</sub> values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives <b>1b</b> and <b>1c</b> as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of <b>1c</b> might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment. |
| first_indexed | 2024-03-09T00:35:37Z |
| format | Article |
| id | doaj.art-91b37c5f24d64da8ae35da3bc28c5c4a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T00:35:37Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-91b37c5f24d64da8ae35da3bc28c5c4a2023-12-11T18:13:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01225224310.3390/ijms22052243New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma CellsEva Schaller0Andi Ma1Lisa Chiara Gosch2Adrian Klefenz3David Schaller4Nils Goehringer5Leonard Kaps6Detlef Schuppan7Andrea Volkamer8Rainer Schobert9Bernhard Biersack10Bianca Nitzsche11Michael Höpfner12Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, GermanyInstitute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, GermanyInstitute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, GermanyInstitute of Translational Immunology, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, GermanyIn Silico Toxicology and Structural Bioinformatics, Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, GermanyInstitute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, GermanyInstitute of Translational Immunology, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, GermanyInstitute of Translational Immunology, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, GermanyIn Silico Toxicology and Structural Bioinformatics, Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, GermanyOrganic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, GermanyOrganic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, GermanyInstitute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, GermanyInstitute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, GermanyNew 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC<sub>50</sub> values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives <b>1b</b> and <b>1c</b> as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of <b>1c</b> might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment.https://www.mdpi.com/1422-0067/22/5/2243hepatomaanticancer drugsthiophenetyrphostinVEGFR inhibitionCAM assay |
| spellingShingle | Eva Schaller Andi Ma Lisa Chiara Gosch Adrian Klefenz David Schaller Nils Goehringer Leonard Kaps Detlef Schuppan Andrea Volkamer Rainer Schobert Bernhard Biersack Bianca Nitzsche Michael Höpfner New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells International Journal of Molecular Sciences hepatoma anticancer drugs thiophene tyrphostin VEGFR inhibition CAM assay |
| title | New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells |
| title_full | New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells |
| title_fullStr | New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells |
| title_full_unstemmed | New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells |
| title_short | New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells |
| title_sort | new 3 aryl 2 2 thienyl acrylonitriles with high activity against hepatoma cells |
| topic | hepatoma anticancer drugs thiophene tyrphostin VEGFR inhibition CAM assay |
| url | https://www.mdpi.com/1422-0067/22/5/2243 |
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