Aromatic extended bisamidines: Synthesis, inhibition of topoisomerases, and anticancer cytotoxicity in vitro

A series of four aromatic extended bisamidines (12-15) differing in the nat ure of their terminal basic side chains were synthesized and evaluated for cytotoxic activity in MCF-7 cultured breast cancer cells. The concentration s of 12, 13, 14, and 15 needed to inhibit [H-3]thymidine incorporation Into DNA by 50% (IC50) were found to be 53 muM, 85 muM, 77 muM, and 97 muM, res pectively. To test whether cytotoxic properties were related to DNA-binding and topoisomerase action, the bisamidines 12-15 were evaluated in a cell-f ree system. Data from the ethidium displacement assay showed that bisamidin es 12-15 have significant affinity for DNA and show moderate specificity fo r AT base pairs. In the topoisomerase II assay, the relaxation of DNA was i nhibited with all four drugs and the extent of inhibition was directly prop ortional to the drug concentration. This suggests that DNA binding may be i mplicated in the cytotoxicity of these bisamidines, possibly by inhibiting interactions between topoisomerase II and their DNA targets.