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Development of an Efficient Dual‐Action GST‐Inhibiting Anticancer Platinum(IV) Prodrug
Author(s) -
Lee Keefe Guang Zhi,
Babak Maria V.,
Weiss Andrea,
Dyson Paul J.,
NowakSliwinska Patrycja,
Montagner Diego,
Ang Wee Han
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800105
Subject(s) - prodrug , cisplatin , chemistry , in vivo , cytotoxicity , in vitro , pharmacology , conjugate , cytotoxic t cell , glutathione , stereochemistry , ligand (biochemistry) , biochemistry , cancer research , biology , chemotherapy , enzyme , medicine , receptor , mathematical analysis , microbiology and biotechnology , mathematics
Abstract The cytotoxicity of cisplatin (cDDP) is enhanced when co‐administered with ethacrynic acid (EA), a glutathione S‐transferase (GST) inhibitor. A Pt 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 Pt II species to exert a synergistic cytotoxic effect. In this study, a redesigned Pt IV 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 Pt II 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.