Book of Abstracts - Ruhr-Universität Bochum

P-20
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Cytotoxic Apoptosis-Inducing Organometallic Rhodium Complexes with
Substituted Polypyridyl Ligands
Yvonne Geldmacher, a Riccardo Rubbiani, b Ingo Ott, b and William S. Sheldrick a*
a Ruhr-Universität Bochum,Faculty of Chemistry and Biochemistry, Department of Analytical
chemistry, Universitätsstr. 150, 44780 Bochum, Germany, b Technical University of Braunschweig,
Department of Pharmaceutical Chemistry, Beethovenstr. 55, 38106 Braunschweig, Germany
E-mail: yvonne.geldmacher@rub.de
The complexes of the type [(η 5 -C5Me5)RhCl(pp)]CF3SO3 (with pp= dpq, dppz, dppn) represent a new
class of cytotoxic substances. Cytotoxicity and cellular uptake studies on the HEK-293, MCF-7 and
HT-29 cell lines have been employed to establish relationships between the structure and the activity
of the complexes. UV/Vis kinetic, thermal denaturation and CD studies have shown, that the prefered
binding mode of the complexes to DNA is intercalation. [(η 5 -C5Me5)RhCl(dppz)]CF3SO3 invokes the
largest increase in Tm with a value 12 °C being recorded for a 1:10 complex/DNA mixture in the
denaturation experiment. In contrast, complexes containing the smaller chelate ligands with pp = en,
bpy and phen exhibit negative ΔTm values, which indicates the presence of a covalent binding mode.
CD spectra for the complex/DNA mixtures with pp = dpq and dppz contain a negative ICD-signal in
the range 280-300 nm, which also indicates intercalation. Viscosity measurements also confirm the
conclusions from UV/Vis and CD studies. 1
100
Figure 1: crystal structure of Figure 2: DNA-fragmentation after a 72 h treatment of
[(η 5 -C5Me5)RhCl(5,6- Me2phen)]CF3SO3 BJAB cells with [(η 5 -C5Me5)RhCl(5,6- Me2phen)]CF3SO3 at different
concentrations
The biological activity also correlates with the lipophilicity and thereby with the size of the
polypyridyl ligand. The IC50 values decrease in the series en, bpy>> phen,dpq > dppz > dppn. One
goal of our ongoing studies is to improve the cell selectivity and identify lead substances by varying
the ligands L and pp in complexes [(η 5 -C5Me5)RhL(pp)](CF3SO3)n. It has previously been shown that
there are significant differences between the cytotoxicities of Pt(II) complexes with methylated 1,10phenanthroline
ligands. 2 We now report studies of the biological activity of [(η 5 -
C5Me5)RhCl(pp)]CF3SO3 complexes containing methylated phenanthroline ligands and other
substituted polypyridyl ligands. Measurements of the LDH release for lymphoma (BJAB) cells after
1h incubation with phen, 5,6-Me2phen and dppz complexes demonstrated that unspecific necrosis is
negligible. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72
h (Figure 2).
References
apoptotic cells [%]
75
50
25
0
1. M.A. Scharwitz, I. Ott, Y. Geldmacher, R. Gust, W.S. Sheldrick, J. Organomet. Chem. 2008, 693,
2299-2309.
2. C.R. Brodie, J.G. Jollins, J.R. Aldrich-Wright, Dalton Trans. 2004, 1145.
78
Co DMSO0.1 1 5 10 25 50 75 100
concentration [µM]