Arene–Ru(II)–chloroquine complexes interact with DNA, induce apoptosis on human lymphoid cell lines and display low toxicity to normal mammalian cells

Abstract

The complexes [Ru(?6-p-cymene)(CQ)Cl2] (1), [Ru(?6-benzene)(CQ)Cl2] (2), [Ru(?6-p-cymene)(CQ)(H2O)2][BF4]2 (3), [Ru(?6-p-cymene)(en)(CQ)][PF6]2 (4), [Ru(?6-p-cymene)(?6-CQDP)][BF4]2 (5) (CQ = chloroquine base; CQDP = chloroquine diphosphate; en = ethylenediamine) interact with DNA to a comparable extent to that of CQ and in analogous intercalative manner with no evidence for any direct contribution of the metal, as shown by spectrophotometric and fluorimetric titrations, thermal denaturation measurements, circular dichroism spectroscopy and electrophoresis mobility shift assays. Complexes 1?5 induced cytotoxicity in Jurkat and SUP-T1 cancer cells primarily via apoptosis. Despite the similarities in the DNA binding behavior of complexes 1?5 with those of CQ the antitumor properties of the metal drugs do not correlate with those of CQ, indicating that DNA is not the principal target in the mechanism of cytotoxicity of these compounds. Importantly, the Ru?CQ complexes are generally less toxic toward normal mouse splenocytes and human foreskin fibroblast cells than the standard antimalarial drug CQDP and therefore this type of compound shows promise for drug development.