Book of Abstracts - Ruhr-Universität Bochum

P-48
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Cytotoxic Organoiridium(III) mono- and bis-intercalators with rigid bridging
ligands of different lengths
Ali M. Nazif a and William S. Sheldrick *a
a Lehrstuhl für Analytische Chemie, Ruhr-Universität Bochum, D-44780 Bochum
We have recently reported significant in vitro activity for members of the organometallic halfsandwich
series [(η 5 -C5Me5)IrCl(pp)] + containing a single polypyridyl ligand (pp = dpq, dppz, dppn).
Their IC50 values towards human MCF-7 (breast carcinoma) and HT-29 cells (colon-carcinoma) lie in
the range 30.3 - 0.12�M and correlate with the size of the polypyridyl ligand, i.e. the IC50 values
decrease significantly in the order dpq > dppz> dppn.
An attractive design strategy to enhance both the affinity and specificity of DNA interactions is to
combine an intercalator with other functionalities such as a second intercalator or a metal fragment
capable of coordinative binding to nucleobases. Bis-intercalators might be expected to exhibit a
greatly increased binding affinity for DNA, which could also lead to improved cytotoxicity owing to
both the increased number of DNA adducts formed and decreased effectiveness of DNA repair
proteins.
These considerations prompted us to investigate the suitability of rigid bridging ligands of different
lengths including pyrazine, 4,4'-bipyridine, trans-1,2-bis(4-pyridyl)ethylene and 1,2-bis(4pyridyl)ethyne
for enabling bis-intercalation of the polypyridyl ligands belonging to the dinuclear
complexes [{(η 5 -C5Me5)Ir(pp)}2(B)](CF3SO3)4 (pp = dpq, dppz, dppn). The interaction of the
complexes with DNA was studied using UV/VIS spectroscopy, circular dichroism, viscosity titrations
and gel electrophoresis. The studies confirm dppz as representing an optimum surface area for
intercalation. In contrast, the dppn-containing complexes prefer surface binding with π-stacking.
Based on these results, our research has focused on dppz-containing complexes which exhibit high
cytotoxicities towards the human cell lines MCF-7 (breast cancer) and HT-29 (colon cancer), with
IC50 values of respectively 3.1 �M and 3.7 �M being observed for the cell lines for B =4,4´-bipyridyl.
Bis-intercalation of the 4,4´-bipyridyl complex was indicated by CD measurements and confirmed by
viscosity titration, where the degree of DNA lengthening was doubled in comparison to an analogous
monointercalator. 1
Conclusive evidence for the bis-intercalative binding mode of [{(η 5 -C5Me5)Ir(dppz)}2(4,4´bpy)](CF3SO3)4
was also obtained from an NMR-NOESY study of its interaction with the
decanucleotide d(5´-CGCGTAGGCC-3´). The observed interruptions of intramolecular NOE cross
peaks between nucleobase H6/H8 protons and sugar H2´/H2´´ protons of the preceding nucleobase are
in accordance with a bis-intercalation mode sandwiching the G4/C17 and T5/A16 base pairs. A range
of intermolecular NOE cross peaks are also observed between the dppz complex and decanucleotide
protons. These include contacts between the H3 and H4 protons of one dppz ligand to T5-H2´ and
between the H3´ and H4´ protons of the other dppz ligand to C17-H2´. The presence of these and other
NOE cross peaks underlines the degree of detailed information that can be obtained from the NOESY
spectrum, and allows a satisfactory refinement of the NMR structure of the complex-DNA adduct.
References
1. M.A. Nazif, J.-A. Bangert, I. Ott, R. Gust, R. Stoll, W. S. Sheldrick, J. Inorg. Biochem. 2009, 103, 1405-
1414.
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