Pt(IV) complexes as prodrugs for cisplatin

Yi Shi, Shu An Liu, Deborah J. Kerwood, Jerry Goodisman, James C. Dabrowiak

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112 Scopus citations

Abstract

The antitumor effects of platinum(IV) complexes, considered prodrugs for cisplatin, are believed to be due to biological reduction of Pt(IV) to Pt(II), with the reduction products binding to DNA and other cellular targets. In this work we used pBR322 DNA to capture the products of reduction of oxoplatin, c,t,c-[PtCl 2(OH) 2(NH 3) 2], 3, and a carboxylate-modified analog, c,t,c-[PtCl 2(OH)(O 2CCH 2CH 2CO 2H)(NH 3) 2], 4, by ascorbic acid (AsA) or glutathione (GSH). Since carbonate plays a significant role in the speciation of platinum complexes in solution, we also investigated the effects of carbonate on the reduction/DNA-binding process. In pH 7.4 buffer in the absence of carbonate, both 3 and 4 are reduced by AsA to cisplatin (confirmed using 195Pt NMR), which binds to and unwinds closed circular DNA in a manner consistent with the formation of the well-known 1, 2 intrastrand DNA crosslink. However, when GSH is used as the reducing agent for 3 and 4, 195Pt NMR shows that cisplatin is not produced in the reaction medium. Although the Pt(II) products bind to closed circular DNA, their effect on the mobility of Form I DNA is different from that produced by cisplatin. When physiological carbonate is present in the reduction medium, 13C NMR shows that Pt(II) carbonato complexes form which block or impede platinum binding to DNA. The results of the study vis-à-vis the ability of the Pt(IV) complexes to act as prodrugs for cisplatin are discussed.

Original languageEnglish (US)
Pages (from-to)6-14
Number of pages9
JournalJournal of Inorganic Biochemistry
Volume107
Issue number1
DOIs
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

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    Shi, Y., Liu, S. A., Kerwood, D. J., Goodisman, J., & Dabrowiak, J. C. (2012). Pt(IV) complexes as prodrugs for cisplatin. Journal of Inorganic Biochemistry, 107(1), 6-14. https://doi.org/10.1016/j.jinorgbio.2011.10.012