TY - JOUR
T1 - Multi-action platinum(IV) prodrugs conjugated with COX-inhibiting NSAIDs
AU - Liu, Xiao
AU - Wenisch, Dominik
AU - Dahlke, Philipp
AU - Jordan, Paul M.
AU - Jakupec, Michael A.
AU - Kowol, Christian R.
AU - Liebing, Phil
AU - Werz, Oliver
AU - Keppler, Bernhard K.
AU - Weigand, Wolfgang
N1 - Accession Number: WOS:001019621200001
PubMed ID: 37295160
PY - 2023/9/5
Y1 - 2023/9/5
N2 - 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.
AB - 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.
KW - Anticancer
KW - Apoptosis
KW - Cyclooxygenase inhibition
KW - NSAIDs
KW - Pt(IV) prodrugs
UR - http://www.scopus.com/inward/record.url?scp=85161350860&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2023.115515
DO - 10.1016/j.ejmech.2023.115515
M3 - Article
C2 - 37295160
AN - SCOPUS:85161350860
SN - 0223-5234
VL - 257
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 115515
ER -
