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

GND
1306963060
Affiliation
Institute for Inorganic and Analytical Chemistry, Friedrich Schiller Universität Jena
Liu, Xiao;
ORCID
0000-0001-5305-2048
Affiliation
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna
Wenisch, Dominik;
GND
1325511994
Affiliation
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena
Dahlke, Philipp;
GND
1249528054
ORCID
0000-0002-8364-4236
Affiliation
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena
Jordan, Paul M.;
ORCID
0000-0001-7945-1426
Affiliation
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna
Jakupec, Michael A.;
ORCID
0000-0002-8311-1632
Affiliation
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna
Kowol, Christian R.;
GND
1276149425
Affiliation
Institute for Inorganic and Analytical Chemistry, Friedrich Schiller Universität Jena
Liebing, Phil;
GND
1022335375
Affiliation
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena
Werz, Oliver;
ORCID
0000-0003-0877-1822
Affiliation
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna
Keppler, Bernhard K.;
GND
1062586395
ORCID
0000-0001-5177-1006
Affiliation
Institute for Inorganic and Analytical Chemistry, Friedrich Schiller Universit¨at Jena
Weigand, Wolfgang

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.

Cite

Citation style:
Could not load citation form.

Rights

Use and reproduction: