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Initially, ligands <jats:bold>L<\/jats:bold><jats:sup><jats:italic><jats:bold>EE<\/jats:bold><\/jats:italic><\/jats:sup> (containing two ethacrynic acid units), <jats:bold>L<\/jats:bold><jats:sup><jats:italic><jats:bold>EF<\/jats:bold><\/jats:italic><\/jats:sup> (ethacrynic acid+flurbiprofen) and <jats:bold>L<\/jats:bold><jats:sup><jats:italic><jats:bold>EB<\/jats:bold><\/jats:italic><\/jats:sup> (ethacrynic acid+biotin) were obtained in moderate to good yields from 2,2\u2032\u2010bipyridine\u20104,4\u2032\u2010dicarboxylic acid. Subsequent reaction of the ligands with [PtCl<jats:sub>2<\/jats:sub>(DMSO)<jats:sub>2<\/jats:sub>] afforded complexes [PtCl<jats:sub>2<\/jats:sub>(<jats:bold>L<\/jats:bold><jats:sup><jats:italic><jats:bold>EE<\/jats:bold><\/jats:italic><\/jats:sup>)] (<jats:bold>2<\/jats:bold>), [PtCl<jats:sub>2<\/jats:sub>(<jats:bold>L<\/jats:bold><jats:sup><jats:italic><jats:bold>EF<\/jats:bold><\/jats:italic><\/jats:sup>)] (<jats:bold>3<\/jats:bold>) and [PtCl<jats:sub>2<\/jats:sub>(<jats:bold>L<\/jats:bold><jats:sup><jats:italic><jats:bold>EB<\/jats:bold><\/jats:italic><\/jats:sup>)] (<jats:bold>4<\/jats:bold>) in high yields. All compounds were fully characterized by analytical and spectroscopic methods. Complexes\u2005<jats:bold>2<\/jats:bold>\u2013<jats:bold>4<\/jats:bold> are highly stable in water\/DMSO solution at 37\u2009\u00b0C after 72\u2005h, 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\u2010tumourigenic HEK293 cells. In particular, the combination of ethacrynic acid and flurbiprofen in <jats:bold>3<\/jats:bold> overcomes cisplatin\u2010based resistance and provides strong cancer cell selectivity. Enzyme inhibition assays on human GST P1 and human COX\u20102 and cross\u2010experiments with complex\u2005<jats:bold>1<\/jats:bold>, analogous to <jats:bold>2<\/jats:bold>\u2013<jats:bold>4<\/jats:bold> but lacking bio\u2010groups, revealed a clear synergy between the Pt<jats:sup>II<\/jats:sup> frame and the bioactive organic components.<\/jats:p>","DOI":"10.1002\/chem.202003199","type":"journal-article","created":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T08:15:20Z","timestamp":1606724120000},"page":"17525-17535","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Bis\u2010conjugation of Bioactive Molecules to Cisplatin\u2010like Complexes through (2,2\u2032\u2010Bipyridine)\u20104,4\u2032\u2010Dicarboxylic Acid with Optimal Cytotoxicity Profile Provided by the Combination Ethacrynic Acid\/Flurbiprofen"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9276-0095","authenticated-orcid":false,"given":"Lorenzo","family":"Biancalana","sequence":"first","affiliation":[{"name":"Dipartimento di Chimica e Chimica Industriale Universit\u00e0 di Pisa  Via G. 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