DNA binding studies of ruthenium(II) dipyridotetrahydrophenazine complexes

152

Journal of Inorganic Biochemistry 96 (2003)

In search for anticancer compounds; new bis(2-phenylazopyridine) ruthenium(I1) complexes Anna CG Hotze, Leiden University, The Netherlands Jaap G Haasnoot, Leiden University, The Netherlands Jan Reedijk, Leiden University, The Netherlands The a-isomer of the dichlorobis(2-phenylazopyridine) ruthenium(B) complexes, a-[Ru(azpy),Cl,] (a indicates the coordinating pairs Cl, N(py), N(azo) are cis, trans, cis, respectively), shows a remarkably high cytotoxicity against a seriesof tumor-cell lines.[ 1,5] In order to investigate structure-activity relationships, research has been focussed on the investigation of DNAmodel base coordination[2-41 and synthesis of related complexes by variation ofthe azpy ligands and anions. The water solubility of the parent compound has been improved by changing the nature of the anions. A seriesof new water-soluble complexes a-[Ru(azpy),X] with X=(nitrateX, oxalato, malonato and l,l-cyclobutanedicarboxylato (cbdca) (seefigure) has been designed. The cytotoxicity and cellular uptake of these water-soluble complexes have been evaluated in several human tumor cell lines.[5] These complexes display a very high cytotoxicity, comparable to the activity of the anticancer drug cisplatin and even better than the second generation drug carboplatin. Moreover, the high cytotoxicity in A2780cisR, a cisplatin _ resistant cell line, shows that this classof ruthenium complexes might not be influenced by the multifactorial resistance mechanism that affect platinum anticancer agents. References: [l] A.H. Velders, H. Kooijman, A.L. Spek, J.G. Haasnoot, D. de Vos, J. Reedijk, Inorg. Chem. 2000,39,2966-2967. [2] A.C.G. Hotze, A.H. Velders, F. Ugozolli, M. Biagini-Cingi, A.M. Manotti-Lanfredi, J.G. Haasnoot, J. Reedijk, Inorg. Chem. 2000,39,3838-3844 [3] A.C.G. Hotze, M.E.T. Broekhuisen, A.H. Velders, K. v.d. Schilden, J. G. Haasnoot, J. Reedijk, Eur. J. Inorg. Chem. 2002,369-376 [4] A.C.G. Hotze, M.E.T. Broekhuisen, A.H. Velders, H. Kooijman, A.L. Spek, J. G. Haasnoot, J. Reedijk, J. Chem. Sot., Dalton Trans.,. 2002,2809-28 10 [5] A.C.G. Hotze, M. Bacac, A.H. Velders, B.A.J. Jansen, H. Kooijman, A.L. Spek, J.G. Haasnoot, J. Reedijk, J. Med. Chem. 2002, submitted

DNA binding studies of ruthenium(H)

dipyridotetrahydrophenazine

complexes

Warren A Howard, School of Science, Food and Horticulture, University of WesternSydney,Australia Janice R Aldrich-Wright, School of Science, Food and Horticulture, University of WesternSydney,Australia Over the past three decades there has been considerable interest in the DNA binding properties of ruthenium(B) metal complexes. However, despite many publications in the field, studies on specific binding data has remained limited. A series of ruthenium(B) polypyridyl complexes of the type [Ru(L-L),dpqC]‘+, where L-L = 1, IO-phenanthroline (phen), 2,9-dimethyl- 1, lo-phenanthroline (Me,phen), 3,4,7,8-tetramethyl-I,1 O,-phenanthroline (Me,phen), 2,2’-dipyridyl (bipy) or 4,4’-dimethyl-2,2’-dipyridyl (Me,bipy), have been investigated in 100 this work. The equilibrium binding constants (K,) and binding sites 90 (n) were determined by fluorescence and UV-Vis spectroscopy (See 80 Figure). Derivations were conducted following the McGhee and von Hippel method and calculated using non-linear regression (Sigma o zz PlotTMsoftware). p8 50 Figure: A) Fluorescence titration spectra; 3.93 x IO-6M [Ru(bipy),dpqC12+ in 3 mL Phosphate buffer (10 mM sodium phosphate, 100 mM sodium chloride, pH 7.0). 550

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650 700 Wavelargth pm)

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