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

被引：7
作者：
Liu, Xiao [1 ]
Wenisch, Dominik [2 ]
Dahlke, Philipp [3 ]
Jordan, Paul M. [3 ]
Jakupec, Michael A. [2 ,4 ]
Kowol, Christian R. [2 ,4 ]
Liebing, Phil [1 ]
Werz, Oliver [3 ]
Keppler, Bernhard K. [2 ,4 ]
Weigand, Wolfgang [1 ]
机构：
[1] Friedrich Schiller Univ Jena, Inst Inorgan & Analyt Chem, Humboldt Str 8, D-07743 Jena, Germany
[2] Univ Vienna, Inst Inorgan Chem, Fac Chem, Wahringer Str 42, A-1090 Vienna, Austria
[3] Friedrich Schiller Univ Jena, Inst Pharm, Dept Pharmaceut Med Chem, Philosophenweg 14, D-07743 Jena, Germany
[4] Univ Vienna, Res Cluster Translat Canc Therapy Res, Wahringer Str 42, A-1090 Vienna, Austria
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 257卷
关键词：
Pt(IV) prodrugs; NSAIDs; Cyclooxygenase inhibition; Anticancer; Apoptosis; IN-VITRO; CANCER; INFLAMMATION; ACECLOFENAC; GENERATION; MANAGEMENT; MECHANISMS; DELIVERY; ASPIRIN;
D O I：
10.1016/j.ejmech.2023.115515
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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.
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页数：13
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