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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
Author(s) -
Biancalana Lorenzo,
Batchelor Lucinda K.,
Pereira Sarah A. P.,
Tseng PoJen,
Zacchini Stefano,
Pampaloni Guido,
Saraiva Lúcia M. F. S.,
Dyson Paul J.,
Marchetti Fabio
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202003199
Subject(s) - chemistry , flurbiprofen , cytotoxicity , cisplatin , dicarboxylic acid , selectivity , stereochemistry , ligand (biochemistry) , in vitro , 2,2' bipyridine , molecule , bipyridine , combinatorial chemistry , biochemistry , receptor , organic chemistry , pharmacology , catalysis , biology , chemotherapy , crystal structure , genetics
A facile route to Pt II complexes doubly functionalized with bioactive molecules through a bipyridine‐type ligand is described. Initially, ligands L EE (containing two ethacrynic acid units), L EF (ethacrynic acid+flurbiprofen) and L EB (ethacrynic acid+biotin) were obtained in moderate to good yields from 2,2′‐bipyridine‐4,4′‐dicarboxylic acid. Subsequent reaction of the ligands with [PtCl 2 (DMSO) 2 ] afforded complexes [PtCl 2 ( L EE )] ( 2 ), [PtCl 2 ( L EF )] ( 3 ) and [PtCl 2 ( L EB )] ( 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 Pt II frame and the bioactive organic components.