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

Author(s)
Xiao Liu, Dominik Wenisch, Philipp Dahlke, Paul M. Jordan, Michael A. Jakupec, Christian R. Kowol, Phil Liebing, Oliver Werz, Bernhard K. Keppler, Wolfgang Weigand
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.

Organisation(s)
Department of Inorganic Chemistry
External organisation(s)
Friedrich-Schiller-Universität Jena, Research Cluster Translational Cancer Therapy Research
Journal
European Journal of Medicinal Chemistry
Volume
257
ISSN
0223-5234
DOI
https://doi.org/10.1016/j.ejmech.2023.115515
Publication date
09-2023
Peer reviewed
Yes
Austrian Fields of Science 2012
301305 Medical chemistry, 104003 Inorganic chemistry, 301904 Cancer research
Keywords
ASJC Scopus subject areas
Pharmacology, Drug Discovery, Organic Chemistry
Sustainable Development Goals
SDG 3 - Good Health and Well-being
Portal url
https://ucrisportal.univie.ac.at/en/publications/6873ea8d-fdfd-4e92-b9e7-ad69d1e08d41