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Development of an Efficient Dual-Action GST-Inhibiting Anticancer Platinum(IV) Prodrug
Lee, Keefe Guang Zhi; Babak, Maria V; Weiss, A.; Dyson, Paul J; Nowak-Sliwinska, Patrycja; Montagner, Diego; Han Ang, Wee
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.
Keyword(s): Development; Efficient; Dual-Action; GST-Inhibiting; Anticancer; Platinum; IV; Prodrug
Publication Date:
2018
Type: Journal article
Peer-Reviewed: Yes
Institution: Maynooth University
Citation(s): 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
Publisher(s): Wiley
File Format(s): other
Related Link(s): http://mural.maynoothuniversity.ie/13221/1/DM_chemistry_development.pdf
First Indexed: 2020-09-15 06:01:52 Last Updated: 2020-09-15 06:01:52