DNA binding properties and cytotoxic activities of two trinuclear ruthenium(II) polypyridyl complexes

Abstract

The interactions between two trinuclear Ru(II) complexes and calf thymus DNA(CT DNA) were studied via absorption spectroscopy, reverse salt titrations, binding stoichiometry, DNA melting experiments, as well as viscosity measurement. The results indicate that complexes 1 and 2 bind to DNA via the interaction of the planar π-delocalized system of the complexes with intrinsic binding constants of 4.18×10⁵ and 3.85×10⁶ L/mol, respectively, and non-electrostatic binding free energy makes a predominant contribution to the binding free energy. The in vitro cytotoxic activity of complexes 1 and 2 was evaluated by the MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide]_method. Complex 1 shows higher anticancer potency than complex 2 against four tumor cell lines. Further mechanism study indicates that complexes 1 and 2 can cause cell cycle arrest in the G₂/M phase.

Keywords

Ruthenium(II) complex / DNA binding / Cell cycle

References

[1] Chen G J, Qiao X, Qiao P Q, Xu G J, Xu J Y, Tian J L, Gu W, Liu X, Yan S P. J. Inorg. Biochem., 2011, 105: 119.

[2] Zuber G, Quada J C, Hecht S M. J. Am. Chem. Soc., 1998, 120: 9368.

[3] Barve A, Kumbhar A, Bhat M, Joshi B, Butcher R, Sonawane U, Joshi R. Inorg. Chem., 2009, 48: 9120.

[4] Bruijnincx P C, Sadler P J. Curr. Opin. Chem. Biol., 2008, 12: 197.

[5] Kostova I. Curr. Med. Chem., 2006, 13: 1085.

[6] Antonarakis E S, Emadi A. Cancer Chemother. Pharmacol., 2010, 66: 1.

[7] Ang W H, Dyson P J. Eur. J. Inorg. Chem., 2006, 20: 4003.

[8] Tan C P, Lai S S, Wu S H, Hu S, Zhou L J, Chen Y, Wang M X, Zhu Y P, Lian W, Peng W L, Ji L N, Xu A L. J. Med. Chem., 2010, 53: 7613.

[9] Schatzschneider U, Niesel J, Ott I, Gust R, Alborzinia H, Wolfl S. ChemMedChem, 2008, 3: 1104.

[10] Barragán F, López-Senín P, Salassa L, Betanzos-Lara S, Habtemariam A, Moreno V, Sadler P J, Marchán V. J. Am. Chem. Soc., 2011, 133: 14098.

[11] Sun Y, Ojaimi M E, Hammitt R, Thummel R P, Turro C. J. Phys. Chem. B, 2010, 114: 14664.

[12] Rademaker-Lakhai J M, van den Bongard D, Pluim D, Beijnen J H, Schellens J H M. Clin. Cancer Res., 2004, 10: 3717.

[13] Hartinger C G, Jakupec M A, Zorbas-Seifried S, Groessl M, Egger A, Berger W, Zorbas H, Dyson P J, Keppler B K. Chem. Biodiversity, 2008, 5: 2140.

[14] Norden B, Lincoln P, Akerman B, Tuite E. Metal Ions in Biological System: Probing of Nucleic Acids by Metal Ion Complexes of Small Molecules, 1996, New York: Mercel Dekker 177.

[15] Choi S D, Kim M S, Kim S K, Lincoln P, Tuite E, Nordén B. Biochemistry, 1997, 36: 214.

[16] Keene F R, Smith J A, Collins J G. Coord. Chem. Rev., 2009, 253: 2021.

[17] Rajput C, Rutkaite R, Swanson L, Haq I, Thomas J A. Chem. Eur. J., 2006, 12: 4611.

[18] Nordell P, Westerlund F, Wilhelmsson L M, Nordén B, Lincoln P. Angew. Chem. Int. Ed., 2007, 46: 2203.

[19] Xu L, Liao G L, Chen X, Zhao C Y, Chao H, Ji L N. Inorg. Chem. Commun., 2010, 13: 1050.

[20] Marmur J. J. Mol. Biol., 1961, 3: 208.

[21] Reichmann M E, Rice S A, Thomas C A, Doty P. J. Am. Chem. Soc., 1954, 76: 3047.

[22] Wolf A, Shimer G H Jr., Meehan T. Biochemistry, 1987, 26: 6392.

[23] Chaires J B, Dattagupta N, Crothers D M. Biochemistry, 1982, 21: 3933.

[24] Satyanarayana S, Dabrowiak J C, Chaires J B. Biochemistry, 1993, 32: 2573.

[25] Cohen G, Eisenberg H. Biopolymers, 1969, 8: 45.

[26] Job P. Ann. Chim., 1928, 9: 113.

[27] Mosmann T. J. Immunol. Methods, 1983, 65: 55.

[28] Hiort C, Lincoln P, Nordén B. J. Am. Chem. Soc., 1993, 115: 3448.

[29] O’Reilly F M, Kelly J M. J. Phys. Chem. B, 2000, 104: 7206.

[30] Ezadyar S A, Kumbhar A S, Kumbhar A A, Khan A. Polyhedron, 2012, 36: 45.

[31] Eriksson M, Mehmedovic M, Westman G, Akerman B. Electrophoresis, 2005, 26: 524.

[32] Ju C C, Zhang A G, Yuan C L, Zhao X L, Wang K Z. J. Inorg. Biochem., 2011, 105: 435.

[33] O’Reilly F M, Kelly J M. New. J. Chem., 1998, 22: 215.

[34] Onfelt B, Lincoln P, Norden B. J. Am. Chem. Soc., 2001, 123: 3630.

[35] Record M T, Anderson C F, Lohman T M. Rev. Biophys., 1978, 11: 103.

[36] Tselepi-Kalouli E, Katsaros N. J. Inorg. Biochem., 1989, 37: 271.

[37] Neyhart G A, Grover N, Smith S R, Kalsbeck W A, Fairley T A, Cory M, Thorp H H. J. Am. Chem. Soc., 1993, 115: 4423.

[38] Han M J, Duan Z M, Hao Q, Wang K Z. J. Phys. Chem. C, 2007, 111: 16577.

[39] Sigman D S, Mazumder A, Perrin D M. Chem. Rev., 1993, 93: 2295.

[40] Karna P, Sharp S M, Yates C, Prakash S, Aneja R. Mol. Cancer, 2009, 8: 93.