Synthesis, hydrolytic DNA-cleaving activities and cytotoxicities of EDTA analogue-tethered pyrrole-polyamide dimer-based Ce(IV) complexes.

Two EDTA analogue-tethered C2-symmetrical dimeric monopyrrole-polyamide 5 and dipyrrole-polyamide 6, and their corresponding Ce(IV) complexes Ce-5 and Ce-6 were synthesized and fully characterized. Agarose gel electrophoresis studies on pBR322 DNA cleavage indicate that complexes Ce-5 and Ce-6 exhibited potent DNA-cleaving activities under physiological conditions. The maximal first-order rate constants (kmax's) were (0.42 ± 0.02) h(-1) for Ce-5 and (0.52 ± 0.02) h(-1) for Ce-6, respectively, suggesting that both complexes catalyzed the cleavage of supercoiled DNA by up to approximately 10(8)-fold. Complex Ce-6 exhibited ca 10-fold higher overall catalytic activity (kmax/KM) than Ce-5, which may be ascribed to its higher DNA-binding affinity. Inhibition experiments and a model study convincingly suggest that both complexes Ce-5 and Ce-6 functioned as hydrolytic DNA-cleavers. In addition, both complexes were found to display moderate inhibitory activity toward A549 and HepG-2 cells.