Cytotoxic RhodiumIII Polypyridyl Complexes Containing the Trispyrazolylmethane Coligand: Synthesis, DNA Binding Properties and Structure–Activity Relationships

The RhIIIcomplexes of the type [RhClpptpm]2+[pp = bpy, bpm, phen, tap, dpq, dppz] 4–9have been prepared by stepwise treatment of RhCl3·3H2O or mer,cis[RhCl3DMSOκS2DMSOκO] with the appropriate polypyridyl ligand pp followed by the tripodal ligand trispyrazolylmethane tpm. Intermediates of the type [RhCl3CH3OHpp] 1–3with pp = bpy, phen, dpq were also characterized but exhibit either low 3 or no 1, 2 cytotoxicity. Xray structural analyses of [RhClbpytpm][PF6]24and [RhClphentpm][PF6]26were performed, and the interaction of complexes 4–9with DNA was investigated by CD and UVVis spectroscopy and by gel electrophoresis. CD and viscosity studies confirm strong intercalation of dppz complex 9into DNA. Complexes 8and particularly 9IC50= 0.43, 0.37 μM are potent cytotoxic agents towards the human cancer cell lines MCF7 and HT29, whereas respectively little complex 6 or no activity complexes 4, 5, 7 is observed for the other members of the series. Our findings indicate that the cytotoxicity is dependent on the hydrophobicity of both the polypyridyl and the facial coligand in these and other halfsandwich RhIIIcomplexes. Irradiation of bpy compound 4in the presence of plasmid pBR322 for 30 min at 311 nm at a molar ratio of r= 0.1 leads to total conversion of the supercoiled form into the nicked version. Although dppz complex 9also functions as a photonuclease under these conditions, the degree of cleavage is much lower. © WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009