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Unique Use of Alkylation for Chemo‐Redox Activity by a Pt IV Prodrug
Author(s) -
Pathak Rakesh K.,
Dhar Shanta
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201503866
Subject(s) - prodrug , cisplatin , cytotoxicity , chemistry , glutathione , cancer cell , intracellular , cytosol , alkylation , biochemistry , cancer research , pharmacology , cancer , chemotherapy , in vitro , biology , enzyme , catalysis , genetics
Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin‐based therapy. A unique dual‐acting chemotherapeutic modality, Platin‐ B , a prodrug of cisplatin and pipobroman‐mimicking alkylating agent, was constructed to circumvent tumor resistance. Platin‐ B exhibited a superior cytotoxicity profile in cisplatin‐resistant cancer cells. Enhanced activity and the ability to overcome cancer‐induced resistance of Platin‐ B was related to adduct formation with intracellular glutathione, followed by the activity of Platin‐ B on the mitochondria of cells, along with its conventional nuclear activity. Alkylating moieties present on Platin‐ B enhanced its cellular and subcellular concentration and protected it from early drug sequestration by biological thiols.