Development of an Efficient Dual-Action GST-Inhibiting Anticancer Platinum(IV) Prodrug
Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review
Author(s)
Detail(s)
Original language | English |
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Pages (from-to) | 1210-1217 |
Journal / Publication | ChemMedChem |
Volume | 13 |
Issue number | 12 |
Online published | 10 Apr 2018 |
Publication status | Published - 20 Jun 2018 |
Externally published | Yes |
Link(s)
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.
In: ChemMedChem, Vol. 13, No. 12, 20.06.2018, p. 1210-1217.
Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review