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

    Lee, Keefe Guang Zhi and Babak, Maria V and Weiss, A. and Dyson, Paul J and Nowak-Sliwinska, Patrycja and Montagner, Diego and Han Ang, Wee (2018) Development of an Efficient Dual-Action GST-Inhibiting Anticancer Platinum(IV) Prodrug. ChemMedChem, 13. pp. 1210-1217. ISSN 1860-7187

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    The cytotoxicity of cisplatin (cDDP) is enhanced when co-administered with ethacrynic acid (EA), a glutathione S-transferase (GST) inhibitor.APt 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 PtII species to exert a synergistic cytotoxic effect. In this study,aredesigned 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.

    Item Type: Article
    Keywords: Development; Efficient; Dual-Action; GST-Inhibiting; Anticancer; Platinum; IV; Prodrug;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 13221
    Identification Number:
    Depositing User: Diego Montagner
    Date Deposited: 14 Sep 2020 13:39
    Journal or Publication Title: ChemMedChem
    Publisher: Wiley
    Refereed: Yes
    Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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