Details

Autor(en) / Beteiligte

• Lee, Keefe Guang Zhi
• Babak, Maria V.
• Weiss, Andrea
• Dyson, Paul J.
• Nowak‐Sliwinska, Patrycja
• Montagner, Diego
• Ang, Wee Han

Titel

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

Ist Teil von

• ChemMedChem, 2018-06, Vol.13 (12), p.1210-1217

Ort / Verlag

Germany: Wiley Subscription Services, Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• The cytotoxicity of cisplatin (cDDP) is enhanced when co‐administered with ethacrynic acid (EA), a glutathione S‐transferase (GST) inhibitor. A PtIV–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 PtII species to exert a synergistic cytotoxic effect. In this study, a redesigned PtIV 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 PtII 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 (∼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. Metal with antitumor mettle: We disclose a novel dual‐action PtIV prodrug based on cisplatin and ethacrynic acid (a glutathione S‐transferase (GST) inhibitor) that shows rapid intracellular reduction, high potency against cisplatin‐sensitive and ‐resistant cancer cells, and that is able to decrease tumor growth in vivo in a chicken embryo model with significantly reduced toxicity and an increased embryo survival rate.