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

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

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Author(s)

  • Keefe Guang Zhi Lee
  • Andrea Weiss
  • Paul J. Dyson
  • Patrycja Nowak-Sliwinska
  • Diego Montagner
  • Wee Han Ang

Detail(s)

Original languageEnglish
Pages (from-to)1210-1217
Journal / PublicationChemMedChem
Volume13
Issue number12
Online published10 Apr 2018
Publication statusPublished - 20 Jun 2018
Externally publishedYes

Abstract

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.

Research Area(s)

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

Citation Format(s)

Development of an Efficient Dual-Action GST-Inhibiting Anticancer Platinum(IV) Prodrug. / Lee, Keefe Guang Zhi; Babak, Maria V.; Weiss, Andrea et al.
In: ChemMedChem, Vol. 13, No. 12, 20.06.2018, p. 1210-1217.

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review