Book of Abstracts - Ruhr-Universität Bochum

P-09
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Lead Structure Development of Cytotoxic ([9]aneS3)Rh(III) Compounds
Containing Polypyridyl and Related Ligands
Ruth Bieda, a Andreas Meyer, b Ingo Ott, b and William S. Sheldrick *a
a Ruhr Universität Bochum, Faculty of Chemistry and Biochemistry, Department of Analytical
Chemistry, Universitätsstraße 150, 44780 Bochum, Germany. b Technische Universität Braunschweig,
Institute of Pharmaceutical Chemistry, Beethovenstraße 55 ,38106 Braunschweig, Germany.
E-mail:ruth.bieda@rub.de
Various compounds of the type [RhCl(LL)([9]aneS3)] 2+ (LL = bpy, bpm, phen, tap, dpq, dppz)
containing the tridentate ligand [9]aneS3 were prepared with the goal of establishing structure-activity
relationships with regard to their DNA interaction and cytotoxic activity. 1 Polypyridyl ligands of
different size and length were used as well as diamine and thiaether ligands. Recently published data
have revealed that rhodium(III) complexes containing polypyridyl ligands, which were previously well
known for their intercalating DNA binding properties, also exhibit pronounced cytotoxic activity. 2
For the determination of structure-activity relationships, modified ligands similar to 2,2’-bipyridine
were also investigated. For instance, the organometallic compound containing the ligand 2phenylpyridine
reduces the overall charge of the compounds to +1, a change that could lead to an
improvement in the cellular uptake. The biological properties of this complex were compared with
those of the analogous 2,2’-bipyridine and 2,2’- bipyrimidine compounds.
Interactions of the cytotoxic ([9]aneS3)Rh(III) complexes with DNA were investigated by CD, UV/Vis
and NMR spectroscopy and by gel electrophoresis. Peptide interaction due to covalent binding
following chloride exchange were also established by ESI-MS. IC50 values toward the cancer cells
MCF-7 and HT-29 as well as toward the human embryonic kidney cells HEK-293 were determined
using the crystal violet assay. Apoptosis induction was ascertained for non-adherent BJAB lymphoma
cells and healthy leukocytes. The studies indicate dramatic differences in cytotoxic activity and cell
selectivity within the ligand series LL = bpm, bpy, 2-phenylpyridine. A very high cell selectivity
towards malign lymphoma cells was established for LL = bpm. The complexes induce apoptosis by
the intrinsic mitrochondrial pathway and cause negligible necrosis.
References
S
S
S
Rh
Cl
N
+ 2+
67
Rh
2-phenylpyridine 2,2’-bipyrimidine
1. R. Bieda, I. Ott, M. Dobroschke, A. Prokop, R. Gust, W. S. Sheldrick, J. Inorg. Biochem. 2009,
103, 698-708.
2. (a) M. Harlos, I. Ott, R. Gust, H. Alborzinia, S. Wölfl, A. Kromm, W. S. Sheldrick, J. Med. Chem.
2008, 51, 3924-3933. (b) R. Bieda, I. Ott, R. Gust, W. S. Sheldrick, Eur. J. Inorg. Chem. 2009, 3821-
3831.
S
S
S
Cl
N
N
N
N