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Vol. 53, Issue 5, 846-855, May 1998
ka
Balcarová,
párková,
ákovská,
Institute of Biophysics, Academy of Sciences of the Czech Republic,
CZ-61265 Brno, Czech Republic (Z.B., J.K., A.Z., O.N., V.B.),
Cancer Research Center, c/o Department of Biochemistry and Molecular
Biology, University of Bari, I-70125 Bari, Italy (M.S.S.), and
Department of Pharmaceutical Chemistry, University of Bari, I-70125
Bari, Italy (G.N.)
We synthesized a novel platinum drug,
cis-[PtCl(NH3)2(N7-ACV)]+,
in which ACV is the antiviral drug acyclovir [a deoxyriboguanosine analogue, 9-(2-hydroxyethoxymethyl)guanine]. This new compound exhibits antiviral efficacy in vitro and exhibits an
antitumor activity profile different from that of cisplatin
[Metal-Based Drugs 2:249-256 (1995)]. To
contribute to understanding the mechanisms underlying biological
activity of this new compound, we studied modifications of natural and
synthetic DNAs in cell-free media by
cis-[PtCl(NH3)2(N7-ACV)]+
by various biochemical and biophysical methods. The results indicated that the major DNA adduct of
cis-[PtCl(NH3)2(N7-ACV)]+
was a stable monofunctional adduct at guanine residues. In contrast to
DNA adducts of other monodentate and clinically ineffective platinum(II) compounds, the adducts of
cis-[PtCl(NH3)2(N7-ACV)]+
terminated in vitro DNA and RNA synthesis. In addition,
although DNA adducts of
cis-[PtCl(NH3)2(N7-ACV)]+
and cisplatin were different, some properties of DNA modified by either
compound were qualitatively similar. Such similarities were not noticed
if DNA modifications by other ineffective monofunctional platinum(II)
complexes were investigated. Thus, the DNA binding mode of
monofunctional
cis-[PtCl(NH3)2(N7-ACV)]+
was different from that of other monofunctional but ineffective platinum(II) complexes. It has been suggested that the unique capability of
cis-[PtCl(NH3)2(N7-ACV)]+
to modify DNA may be relevant to a distinct antitumor efficiency of
this novel drug in comparison with cisplatin. It also has been suggested that at least some aspects of DNA interactions of
cis-[PtCl(NH3)2(ACV)]+
revealed in the current study could be exploited in the search for and
development of new antiviral platinum complexes containing, as a part
of the coordination sphere, antiviral nucleosides.
This article has been cited by other articles:
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  K. Neplechová, O. Nováková, A. Habtemariam, B. Watchman, P. J. Sadler, and V. Brabec DNA Interactions of New Antitumor Aminophosphine Platinum(II) Complexes Mol. Pharmacol., July 1, 1999; 56(1): 20 - 30. [Abstract] [Full Text]
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