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.
Keywords:
cancer; cytotoxicity; medicinal chemistry; platinum; redox chemistry.
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Cell Line, Tumor
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Chickens
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Chorioallantoic Membrane / drug effects
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Coordination Complexes / chemical synthesis
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Coordination Complexes / chemistry
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Coordination Complexes / pharmacology
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Coordination Complexes / therapeutic use
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Enzyme Assays
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use*
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Ethacrynic Acid / analogs & derivatives
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Ethacrynic Acid / chemical synthesis
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Ethacrynic Acid / pharmacology
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Ethacrynic Acid / therapeutic use
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Glutathione Transferase / antagonists & inhibitors*
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Humans
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Ligands
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Organoplatinum Compounds / chemical synthesis
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Organoplatinum Compounds / chemistry
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Organoplatinum Compounds / pharmacology
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Organoplatinum Compounds / therapeutic use*
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Prodrugs / chemical synthesis
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Prodrugs / chemistry
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Prodrugs / pharmacology
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Prodrugs / therapeutic use*
Substances
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Antineoplastic Agents
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Coordination Complexes
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Enzyme Inhibitors
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Ligands
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Organoplatinum Compounds
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Prodrugs
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Glutathione Transferase
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Ethacrynic Acid