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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
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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.
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Keyword(s):
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Development; Efficient; Dual-Action; GST-Inhibiting; Anticancer; Platinum; IV; Prodrug |
Publication Date:
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2018 |
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Type:
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Journal article |
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Peer-Reviewed:
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Yes |
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Institution:
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Maynooth University |
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Citation(s):
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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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Publisher(s):
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Wiley |
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File Format(s):
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other |
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Related Link(s):
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http://mural.maynoothuniversity.ie/13221/1/DM_chemistry_development.pdf |
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First Indexed:
2020-09-15 06:01:52 Last Updated:
2020-09-15 06:01:52 |
