Development of Zeise’s Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors
Zeise’s salt derivatives of the potassium trichlorido[η<sup>2</sup>-((prop-2-en/but-3-en)-1-yl)-2-acetoxybenzoate]platinate(II) type (ASA-Prop-PtCl<sub>3</sub>/ASA-But-PtCl<sub>3</sub> derivatives) were synthesized and characterized regarding their structure, stab...
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MDPI AG
2023-05-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/6/1573 |
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| author | Alexander Weninger Jessica Sagasser Victoria Obermoser Josef Egger Susanna Wisboeck Qianqian Qiu Miriam Ladstaetter Andrea Cucchiaro Klaus Wurst Daniel Baecker Ronald Gust |
| author_facet | Alexander Weninger Jessica Sagasser Victoria Obermoser Josef Egger Susanna Wisboeck Qianqian Qiu Miriam Ladstaetter Andrea Cucchiaro Klaus Wurst Daniel Baecker Ronald Gust |
| author_sort | Alexander Weninger |
| collection | DOAJ |
| description | Zeise’s salt derivatives of the potassium trichlorido[η<sup>2</sup>-((prop-2-en/but-3-en)-1-yl)-2-acetoxybenzoate]platinate(II) type (ASA-Prop-PtCl<sub>3</sub>/ASA-But-PtCl<sub>3</sub> derivatives) were synthesized and characterized regarding their structure, stability, and biological activity. It is proposed that the leads ASA-Prop-PtCl<sub>3</sub> and ASA-But-PtCl<sub>3</sub> interfere with the arachidonic acid cascade as part of their mode of action to reduce the growth of COX-1/2-expressing tumor cells. With the aim to increase the antiproliferative activity by strengthening the inhibitory potency against COX-2, F, Cl, or CH<sub>3</sub> substituents were introduced into the acetylsalicylic acid (ASA) moiety. Each structural modification improved COX-2 inhibition. Especially compounds with F substituents at ASA-But-PtCl<sub>3</sub> reached the maximum achievable inhibition of about 70% already at 1 µM. The PGE<sub>2</sub> formation in COX-1/2-positive HT-29 cells was suppressed by all F/Cl/CH<sub>3</sub> derivatives, indicating COX inhibitory potency in cellular systems. The CH<sub>3</sub>-bearing complexes showed the highest cytotoxicity in COX-1/2-positive HT-29 cells with IC<sub>50</sub> values of 16–27 µM. In COX-negative MCF-7 cells, they were 2–3-fold less active. These data clearly demonstrate that it is possible to increase the cytotoxicity of ASA-Prop-PtCl<sub>3</sub> and ASA-But-PtCl<sub>3</sub> derivatives by enhancing COX-2 inhibition. |
| first_indexed | 2024-03-11T02:03:11Z |
| format | Article |
| id | doaj.art-66cca148dea746e4998eb700fd975237 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T02:03:11Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-66cca148dea746e4998eb700fd9752372023-11-18T12:03:23ZengMDPI AGPharmaceutics1999-49232023-05-01156157310.3390/pharmaceutics15061573Development of Zeise’s Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX InhibitorsAlexander Weninger0Jessica Sagasser1Victoria Obermoser2Josef Egger3Susanna Wisboeck4Qianqian Qiu5Miriam Ladstaetter6Andrea Cucchiaro7Klaus Wurst8Daniel Baecker9Ronald Gust10Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaDepartment of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaDepartment of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI—Center for Molecular Biosciences Innsbruck, CCB—Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaZeise’s salt derivatives of the potassium trichlorido[η<sup>2</sup>-((prop-2-en/but-3-en)-1-yl)-2-acetoxybenzoate]platinate(II) type (ASA-Prop-PtCl<sub>3</sub>/ASA-But-PtCl<sub>3</sub> derivatives) were synthesized and characterized regarding their structure, stability, and biological activity. It is proposed that the leads ASA-Prop-PtCl<sub>3</sub> and ASA-But-PtCl<sub>3</sub> interfere with the arachidonic acid cascade as part of their mode of action to reduce the growth of COX-1/2-expressing tumor cells. With the aim to increase the antiproliferative activity by strengthening the inhibitory potency against COX-2, F, Cl, or CH<sub>3</sub> substituents were introduced into the acetylsalicylic acid (ASA) moiety. Each structural modification improved COX-2 inhibition. Especially compounds with F substituents at ASA-But-PtCl<sub>3</sub> reached the maximum achievable inhibition of about 70% already at 1 µM. The PGE<sub>2</sub> formation in COX-1/2-positive HT-29 cells was suppressed by all F/Cl/CH<sub>3</sub> derivatives, indicating COX inhibitory potency in cellular systems. The CH<sub>3</sub>-bearing complexes showed the highest cytotoxicity in COX-1/2-positive HT-29 cells with IC<sub>50</sub> values of 16–27 µM. In COX-negative MCF-7 cells, they were 2–3-fold less active. These data clearly demonstrate that it is possible to increase the cytotoxicity of ASA-Prop-PtCl<sub>3</sub> and ASA-But-PtCl<sub>3</sub> derivatives by enhancing COX-2 inhibition.https://www.mdpi.com/1999-4923/15/6/1573anticancerantiproliferative activitycapillary electrophoresischlorinationCOX-inhibitioncyclooxygenase enzyme |
| spellingShingle | Alexander Weninger Jessica Sagasser Victoria Obermoser Josef Egger Susanna Wisboeck Qianqian Qiu Miriam Ladstaetter Andrea Cucchiaro Klaus Wurst Daniel Baecker Ronald Gust Development of Zeise’s Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors Pharmaceutics anticancer antiproliferative activity capillary electrophoresis chlorination COX-inhibition cyclooxygenase enzyme |
| title | Development of Zeise’s Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors |
| title_full | Development of Zeise’s Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors |
| title_fullStr | Development of Zeise’s Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors |
| title_full_unstemmed | Development of Zeise’s Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors |
| title_short | Development of Zeise’s Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors |
| title_sort | development of zeise s salt derivatives bearing substituted acetylsalicylic acid substructures as cytotoxic cox inhibitors |
| topic | anticancer antiproliferative activity capillary electrophoresis chlorination COX-inhibition cyclooxygenase enzyme |
| url | https://www.mdpi.com/1999-4923/15/6/1573 |
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