ISBN: 978-83-60043-10-3 - eurobic9

Eurobic9, 2-6 September, 2008, Wrocław, Poland
P106. In Silico Approaching to Cisplatin Toxicity Quantum Chemical
Studies on Platinum(II) – Cysteine Systems
J. Kuduk-Jaworska a , I. Jaroszewicz a , J. Jański a , H. Chojnacki b
a Faculty of Chemistry Wroclaw University, F. Joliot-Curie 14, 50-383 Wroclaw, Poland
b Institute of Physical and Theoretical Chemistry, Wrocław University of Technology, Wyb. Wyspiańskiego 27,
50-370 Wrocław, Poland
The differences in therapeutic ability of antitumor drug cisplatin (cis- diamminedichloroplatinum(II)) and its
trans-isomer, are still intriguing for investigators who would like to learn in more detail about the molecular
bases of such behavior [1]. It is well documented that cisplatin has high antitumor activity and strong toxicity,
especially towards kidneys, whereas the trans isomer is therapeutically inefficient and non nephrotoxic.
However, the studies on mechanisms of biological activity of both isomers, performed so far, were focused on
interaction of platinum(II) complexes with DNA as critical target molecule. The problems of cisplatin and its
congeners toxicity, though clinically very important, were far less studied [1]. Similar preferences can be
observed in theoretical approaches [2].
Contrary to this tendency, our interest has been concentrated on the toxicity of cisplatin in comparison with nontoxicity
of its trans isomer. Therefore we evaluated the reactions responsible for harmful biological effects, and
consequently, the impact of platinum(II) complexes on molecules containing sulphur donors became the object
of the presented study.
Our approach relied on applying quantum chemical in silico methodology for the evaluation of "platinum(II) -
cysteine" and its model systems. There were investigated the following systems: (1) a/cisplatin (b/transplatin)
with CH3SH; (2) a/cisplatin (b/transplatin) with cysteine.
The electronic structure for molecular systems has been studied at non-empirical all-electron level by using
density functional (DFT) or Moeller-Plesset (MP2) methods within the correlation consistent cc-pVTZ [3] basis
set. In the case of platinum the widest Huzinaga basis set with polarization functions has been used. In order to
avoid the long optimization process, at the first stage, the optimization was performed at the all-valence
MOPAC-PM6 method [4] following the B3LYP density functional or MP2 formalism [5] in the next step. The
B3LYP [6] density functional was applied using GAUSSIAN-03 program package [7].
Acknowledgements: The numerical calculations have been performed in part at Wrocław Networking and
Supercomputing Center. Wrocław University of Technology support is also acknowledged.
References:
[1] Reedijk, J.; Tauben, J. M. in: Cisplatin. Chemistry and Biochemistry of a Leading Anticancer Drug, Lippert,
B. (Ed.), Wiley-WCH, 1999, 339-362.
[2] Kozelka, J.; ibid, 537-556.
[3] Huzinaga, S.; (Ed.), Gaussian Basis Sets for Molecular Calculations, Elsevier, Amsterdam 1984.
[4] .
[5] Szabó, A.; Ostlund, N.S. Modern Quantum Chemistry, Dover, Mineola 1996.
[6] Becke, A.D.; J Chem Phys, 1993, 98, 5648- 5653.
[7] GAUSSIAN-03, Rev. D-01, Pople, J.A. Gaussian Inc., Pittsburgh, PA, 2004.
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