Cytotoxic Rhodium(III) Polypyridyl Complexes Containing the Tris(pyrazolyl)methane Coligand: Synthesis, DNA Binding Properties and Structure–Activity Relationships

The Rh III complexes of the type [RhCl(pp)(tpm)] 2+ [pp = bpy, bpm, phen, tap, dpq, dppz] 4 – 9 have been prepared by stepwise treatment of RhCl 3 · 3H 2 O or mer , cis ‐[RhCl 3 (DMSO‐κ S ) 2 (DMSO‐κ O )] with the appropriate polypyridyl ligand (pp) followed by the tripodal ligand tris(pyrazolyl)methane (tpm). Intermediates of the type [RhCl 3 (CH 3 OH)(pp)] 1 – 3 with pp = bpy, phen, dpq were also characterized but exhibit either low ( 3 ) or no ( 1 , 2 ) cytotoxicity. X‐ray structural analyses of [RhCl(bpy)(tpm)][PF 6 ] 2 4 and [RhCl(phen)(tpm)][PF 6 ] 2 6 were performed, and the interaction of complexes 4 – 9 with DNA was investigated by CD and UV/Vis spectroscopy and by gel electrophoresis. CD and viscosity studies confirm strong intercalation of dppz complex 9 into DNA. Complexes 8 and particularly 9 (IC 50 = 0.43, 0.37 μ M ) are potent cytotoxic agents towards the human cancer cell lines MCF‐7 and HT‐29, 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 half‐sandwich Rh III complexes. Irradiation of bpy compound 4 in 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 9 also functions as a photonuclease under these conditions, the degree of cleavage is much lower. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)