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.

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

Zacchini S.;
2020

Abstract

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.
2020
Biancalana L.; Batchelor L.K.; Pereira S.A.P.; Tseng P.-J.; Zacchini S.; Pampaloni G.; Saraiva L.M.F.S.; Dyson P.J.; Marchetti F.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/793236
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