Development of an Efficient Dual-Action GST-Inhibiting Anticancer Platinum(IV) Prodrug

作者：Lee Keefe Guang Zhi; Babak Maria V; Weiss Andrea; Dyson Paul J; Nowak Sliwinska Patrycja^*; Montagner Diego^*; Ang Wee Han^*

来源：ChemMedChem, 2018, 13(12): 1210-1217.

DOI：10.1002/cmdc.201800105

• cancer
• cytotoxicity
• medicinal chemistry
• platinum
• redox chemistry

The cytotoxicity of cisplatin (cDDP) is enhanced when co-administered with ethacrynic acid (EA), a glutathione S-transferase (GST) inhibitor. A Pt-IV-EA conjugate containing a cDDP core and two axial ethacrynate ligands (compound 1) was shown to be an excellent inhibitor of GST, but did not readily release a Pt-II species to exert a synergistic cytotoxic effect. In this study, a redesigned Pt-IV construct composed of a cDDP core with one axial ethacrynate ligand and one axial hydroxido ligand (compound 2) was prepared and shown to overcome the limitations of compound 1. The EA ligand in 2 is readily released in vitro together with a cytotoxic Pt-II species derived from cisplatin, working together to inhibit cell proliferation in cDDP-resistant human ovarian cancer cells. The in vitro activity translates well in vivo with 2, showing effective (approximate to 80%) inhibition of tumor growth in a human ovarian carcinoma A2780 tumor model, while showing considerably lower toxicity than cisplatin, thus validating the new design strategy.

• 出版日期2018-6-20