Unique Use of Alkylation for Chemo-Redox Activity by a PtIV Prodrug

Rakesh K. Pathak, Shanta Dhar

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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. A unique dual-acting chemotherapeutic modality Platin-B, a prodrug of PtIV and pipobroman-mimicking alkylating agent, was constructed to act on the mitochondria of cells by using its pendent -Br moieties to induce changes in mitochondrial bioenergetics, formation of repair-inactive Pt-DNA adducts, and ultimately participation in mitochondrial apoptosis and loss of mitochondrial mass to overcome resistance compared to other similar Pt-based compounds.

Original languageEnglish (US)
Pages (from-to)3029-3036
Number of pages8
JournalChemistry - A European Journal
Issue number9
StatePublished - Feb 24 2016
Externally publishedYes


  • DNA repair
  • alkylating agent
  • cancer
  • cisplatin
  • glutathione

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry


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