Multi-action platinum(IV) prodrugs conjugated with COX-inhibiting NSAIDs

Xiao Liu; Dominik Wenisch; Philipp Dahlke; Paul M Jordan; Michael A Jakupec; Christian R Kowol; Phil Liebing; Oliver Werz; Bernhard K Keppler; Wolfgang Weigand

doi:10.1016/j.ejmech.2023.115515

Multi-action platinum(IV) prodrugs conjugated with COX-inhibiting NSAIDs

Eur J Med Chem. 2023 Sep 5:257:115515. doi: 10.1016/j.ejmech.2023.115515. Epub 2023 May 26.

Authors

Affiliations

¹ Institute for Inorganic and Analytical Chemistry, Friedrich Schiller Universität Jena, Humboldt Str. 8, 07743, Jena, Germany.
² Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria.
³ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany.
⁴ Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria; Research Cluster 'Translational Cancer Therapy Research', University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria.
⁵ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
⁶ Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria; Research Cluster 'Translational Cancer Therapy Research', University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria. Electronic address: bernhard.keppler@univie.ac.at.
⁷ Institute for Inorganic and Analytical Chemistry, Friedrich Schiller Universität Jena, Humboldt Str. 8, 07743, Jena, Germany. Electronic address: wolfgang.weigand@uni-jena.de.

PMID: 37295160
DOI: 10.1016/j.ejmech.2023.115515

Abstract

In the last decades, inflammation has been recognized as being closely connected to cancer, and joint strategies encompassing chemotherapeutic and anti-inflammatory agents have been extensively studied. In this work, a series of novel cisplatin and oxaliplatin-based Pt(IV) complexes comprising non-steroidal anti-inflammatory drugs (NSAIDs) and their carboxyl ester analogues as axial moieties were synthesized. Several of the cisplatin-based Pt(IV) complexes 22-30 showed increased cytotoxicity in the human cancer cell lines CH1/PA-1, SW480 and A549 compared to the Pt(II) drug. For the most potent complex 26, comprising two aceclofenac (AFC) moieties, the formation of Pt(II)-9-methylguanine (9-MeG) adducts after activation with ascorbic acid (AsA) was proven. Additionally, a significant inhibition of cyclooxygenase (COX) activity and prostaglandin E₂ (PGE₂) production was observed, as well as increased cellular accumulation, depolarization of mitochondrial membranes, and strong proapoptotic potencies in SW480 cells. Overall, these systematic effects shown in vitro confer 26 as a potential anticancer agent combined with anti-inflammatory properties.

Keywords: Anticancer; Apoptosis; Cyclooxygenase inhibition; NSAIDs; Pt(IV) prodrugs.

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Cell Line, Tumor
Cisplatin* / pharmacology
Humans
Platinum / pharmacology
Prodrugs* / pharmacology
Prostaglandin-Endoperoxide Synthases

Substances

Cisplatin
Prodrugs
Platinum
Prostaglandin-Endoperoxide Synthases
Anti-Inflammatory Agents, Non-Steroidal