Selected interactions of cisplatin in cellular environment. Activation of cisplatin and its coordination to the DNA bases and amino acids.

Jaroslav V. Burda

 

Department of Chemical Physics and Optics, Faculty of Mathematics and Physics, Charles University, Ke Karlovu 3, 121 16 Prague 2, Czech Republic.

 

            Solvation effects were studied for cis/transplatin, as well as for some other charged complexes.1 These investigations were performed using very accurate approach and it was found that Pt(NH3)2(OH)2 together with [Pt(NH3)Cl(OH)2]- complex represent the most stable species on the hydration energy surface. A similar hydration energy surface was also calculated for corresponding square planar Pd(II) complexes.2 Obtained energies (heats of solvation) clearly show that the different metal reactivity (Pt(II) versus Pd(II)) to DNA bases is not caused by different thermodynamical properties of these metals but due to  kinetical reaction factors.3 An important role is also played by the solvent environment which was explored using COSMO model.4

Further, the interactions of the square planar Pt(II) complexes with DNA bases, base pairs and aminoacids were examined. The influence of the platinum complexes on tautomer forms of guanine and adenine was established.5 It was found that the adenine imino-tautomer is more stabilized under the influence of charged platinum cations. However, this preference was eliminated for neutral PtCl2(NH3) adduct, giving a similar energy difference between imino- and amino-forms of adenine like in the cas of non-metalated adenine tautomers. On the contrary, guanine keto-form is further stabilized over enol-form under platination.

            A base pair enhancement under platination was also explored.6 Platination causes some geometry distortion in the H-bond arrangement. This effect was also observed for other metals.7-9 It was shown that no (pairwise) base pair enhancement was observed for AT pair. Nevertheless, platinated guanine base exhibits more firmly connection with cytosine.

            Model study on Pt-bridges of the purine DNA bases shows weaker adenine coordination in accord with the other studies in this branch. In dependence on base (guanine or adenine), symmetrical or non-symmetrical arrangement was observed.10,11

            Recently interactions of cisplatin with amino acides cysteine and methionine were performed, clearly pointing on stronger Pt-cysteine binding in comparison with methionine-containing complex. This correspond to the experimentally known fact that irreversible adducts of cisplatin with cysteine are formed in living body on the contrary to creation of reversible Pt-methionine complexes.12 Also, a model for general amino acids interaction was studied where glycine molecule was employed for this purpose.13

        (1)   Burda, J. V.; Zeizinger, M.; Sponer, J.; Leszczynski, J. J. Chem. Phys. 2000, 113, 2224.

        (2)   Zeizinger, M.; Burda, J. V.; Šponer, J.; Kapsa, V.; Leszczynski, J. J. Phys. Chem. A, 2001, 105, 8086.

        (3)   Burda, J. V.; Zeizinger, M.; Leszczynski, J. J. Chem. Phys. 2004, 120, 1253.

        (4)   Burda, J. V.; Zeizinger, M. J. Comput. Chem. 2004, submitted.

        (5)   Burda, J. V.; Šponer, J.; Leszczynski, J. J. Biol. Inorg. Chem. 2000, 5, 178.

        (6)   Burda, J. V.; Šponer, J.; Leszczynski, J. Phys. Chem. Chem. Phys. 2001, 3, 4404.

        (7)   Burda, J. V.; Šponer, J.; Leszczynski, J.; Hobza, P. J. Phys. Chem. B 1997, 101, 9670.

        (8)   Šponer, J.; Burda, J. V.; Sabat, M.; Leszczynski, J.; Hobza, P. J. Phys. Chem. A 1998, 102, 5951.

        (9)   Šponer, J.; Sabat, M.; Burda, J. V.; Leszczynski, J.; Hobza, P. J. Phys. Chem. B 1999, 103, 2528.

        (10) Burda, J. V.; Leszczynski, J. Inorg. Chem. 2003, 42., 7162.

        (11) Zeizinger, M.; Burda, J. V.; Leszczynski, J. PCCP 2004, 6, 000.

        (12) Burda, J. V.; Zimmermann, T.; Zeizinger, M.; Leszczynski, J. 2004.

        (13) Burda, J. V.; Orozco, M. 2004.