Monofunctional platinum amine complexes destabilize DNA significantly

Cornelia Bauer, Tal Peleg-Shulman, Dan Gibson, Andrew H.J. Wang

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

Both cis-[Pt(NH3)2(4-Me-Py)Cl]+ and trans-[Pt(NH3)2(4-Me-Py)Cl]+ bind DNA covalently at the N7 site of guanine residues forming mono-dentate adducts. However, like cisplatin and transplatin, only the cis isomer has anti-cancer activity, whereas the trans-isomer does not. In order to understand the molecular basis of the different activities associated with cis-[Pt(NH3)2(4-Me-Py)Cl]+ and trans-[Pt(NH3)2(4-Me-Py)Cl]+, the interactions of these two platinum compounds with the DNA heptamer CCTG*TCC:GGACAGG duplex (G* is the platinated guanine) have been examined. The reaction rate of cis-[Pt(NH3)2(4-Me-Py)Cl]+ with the single-stranded CCTGTCC is significantly faster than that of the trans isomer. The solution structure of the platinum-DNA adducts has been studied by two-dimensional NMR spectroscopy. Both the cis-platinum adducts and the trans-platinum adducts destabilize the DNA duplex significantly. The melting temperature (T(m)) of the platinated heptamer duplex is estimated to be 10°C lower than for the unplatinated duplex by NMR. At 2°C, the base pairs located on the 5' side of the oligonucleotide, beyond the platinum lesion site, are disrupted. Over time, the platinum-DNA complex decomposes and the cis-[Pt(NH3)2(4-Me-Py)] platinum complex is gradually detached from DNA. No interstrand crosslinking is observed. The biological implications of the structural studies are discussed.

Original languageEnglish
Pages (from-to)253-260
Number of pages8
JournalEuropean Journal of Biochemistry
Volume256
Issue number2
DOIs
Publication statusPublished - Sep 1 1998
Externally publishedYes

Keywords

  • Anti-cancer
  • Cisplatin
  • DNA
  • Methylpyridine
  • NMR

ASJC Scopus subject areas

  • Biochemistry

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