Bis‐conjugation of Bioactive Molecules to Cisplatin‐like Complexes through (2,2′‐Bipyridine)‐4,4′‐Dicarboxylic Acid with Optimal Cytotoxicity Profile Provided by the Combination Ethacrynic Acid/Flurbiprofen

A facile route to PtII complexes doubly functionalized with bioactive molecules through a bipyridine‐type ligand is described. Initially, ligands LEE (containing two ethacrynic acid units), LEF (ethacrynic acid+flurbiprofen) and LEB (ethacrynic acid+biotin) were obtained in moderate to good yields f...

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Published in:Chemistry : a European journal 2020-12, Vol.26 (72), p.17525-17535
Main Authors: Biancalana, Lorenzo, Batchelor, Lucinda K., Pereira, Sarah A. P., Tseng, Po‐Jen, Zacchini, Stefano, Pampaloni, Guido, Saraiva, Lúcia M. F. S., Dyson, Paul J., Marchetti, Fabio
Format: Article
Language:English
Subjects:
2,2'-Dipyridyl - chemistry
Acids
anticancer agents
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Biocompatibility
bioinorganic chemistry
Biological activity
Biotin
Cell culture
Cell Line, Tumor
Chemistry
Chemotherapy
Cisplatin
Cisplatin - pharmacology
Cisplatin - therapeutic use
Conjugation
Cytotoxicity
Dicarboxylic acids
Ethacrynic acid
Ethacrynic Acid - pharmacology
Ethacrynic Acid - therapeutic use
Female
Flurbiprofen
Flurbiprofen - therapeutic use
HEK293 Cells
Humans
ligand design
Ligands
Ovarian Neoplasms - drug therapy
platinum
Selectivity
Toxicity
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Summary:A facile route to PtII complexes doubly functionalized with bioactive molecules through a bipyridine‐type ligand is described. Initially, ligands LEE (containing two ethacrynic acid units), LEF (ethacrynic acid+flurbiprofen) and LEB (ethacrynic acid+biotin) were obtained in moderate to good yields from 2,2′‐bipyridine‐4,4′‐dicarboxylic acid. Subsequent reaction of the ligands with [PtCl2(DMSO)2] afforded complexes [PtCl2(LEE)] (2), [PtCl2(LEF)] (3) and [PtCl2(LEB)] (4) in high yields. All compounds were fully characterized by analytical and spectroscopic methods. Complexes 2–4 are highly stable in water/DMSO solution at 37 °C after 72 h, whereas progressive release of the bioactive fragments was detected in a cell culture medium. The compounds were assessed for their in vitro antiproliferative activity towards tumorigenic A2780, A2780cisR and Y79 cells and non‐tumourigenic HEK293 cells. In particular, the combination of ethacrynic acid and flurbiprofen in 3 overcomes cisplatin‐based resistance and provides strong cancer cell selectivity. Enzyme inhibition assays on human GST P1 and human COX‐2 and cross‐experiments with complex 1, analogous to 2–4 but lacking bio‐groups, revealed a clear synergy between the PtII frame and the bioactive organic components. Two‐pronged approach: A facile method to tether two different bioactive molecules to the [PtCl2] fragment through modified bipyridine‐type ligands is described. A combination of ethacrynic acid and flurbiprofen residues overcomes cisplatin‐based resistance and provides strong cancer cell selectivity. Enzyme inhibition assays and cross‐experiments with an analogous complex lacking bio‐groups revealed a clear synergy between the PtII unit and the bioactive organic components.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.202003199