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(η6-p-cymene)(CQ)Cl2] (1), [Ru(η6-benzene)(CQ)Cl2] (2), [Ru(η6-p-cymene)(CQ)(H2O)2][BF4]2 (3), [Ru(η6- p-cymene)(en)(CQ)][PF6]2 (4), [Ru(η6-p-cymene)(η6-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.

Analysis of the cytotoxic effects of ruthenium–ketoconazole and ruthenium–clotrimazole complexes on cancer cells

“…For some time, we have been designing potential chemotherapeutics based on the metal-drug synergism (Martinez et al 2012; Martinez et al 2010; Rademaker-Lakhai et al 2004; Rajapakse et al 2009; Strasberg et al 2004), which may be achieved by combining a drug of known therapeutic value with a biologically relevant metal in a single molecule (Sanchez-Delgado et al 2004). Such combinations can lead to new chemical entities with enhanced activity, decreased toxicity, and more controlled pharmacokinetic properties than each separate component, or than the mere physical combination of two drugs.…”

“…Arene-ruthenium “semi-sandwich” compounds like [Ru(η 6 -arene)(X)(Y–Z)] (where Y–Z is a chelating ligand, and X is monoanionic ligand), and related derivatives incorporating the 1,3,5-triaza-7-phosphaadamantane (PTA) ligand (Aird et al 2002; Dougan et al 2006; Morbidelli et al 2003; Morris et al 2001; Scolaro et al 2005; Wang et al 2005) also display very interesting antitumor activities. In our search for metal-drug synergy, we synthesized a series of arene-Ru-chloroquine complexes that proved to be active against Jurkat human T lymphocyte leukemia and SUP-T1 lymphoma cell lines; we also demonstrated that induction of apoptosis is the main path for cell death in these cases (Martinez et al 2010). The complex [Ru(η 6 -arene)Cl 2 (CQ)], also proved to be active in vitro against dedifferentiated liposarcoma (LS141), a type of tumor for which no chemotherapy is available (Rajapakse et al 2009)…”

Synthesis and in vitro Anticancer Activity of Ruthenium–Cymene Complexes with Cyclohexyl‐Functionalized Ethylenediamine‐N,N′‐diacetate‐Type Ligands

“…Accordingly, a significant increase in the activation of caspases (apoptosis-executing cysteine proteases) [23] was observed in cells treated with compound 4 (Figure 2 c). Consistent with the pro-apoptotic activity of Ru-arene compounds [24] and KP1019, a Rubased compound that has entered clinical trials, [25] these data indicate that the anticancer activity of Ru complexes with esters of (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid as chelating ligands is mediated predominantly through the induction of apoptosis without causing significant cell membrane damage. The induction of apoptosis is frequently associated with mitochondrial depolarization, which is one of the crucial events leading to caspase activation.…”

“…The doubling times of HL-60, K562, REH, C6, L929, and B16 cell lines were 26,19,23,24,26, and 17 h, respectively. Peripheral blood mononuclear cells (PBMC) were obtained from the venous blood of seven leukemic patients (two with de novo untreated acute myeloid leukemia, two with chronic myeloid leukemia in chronic phase before treatment, and three in acute blast phase of myeloid transformation of chronic myeloid leukemia) from the Outpatient Clinic of the Outpatient & Diagnostic Department, Clinic of Hematology, Clinical Center of Serbia, Belgrade.…”

Cell Cycle Arrest, Cytotoxicity, Apoptosis, DNA‐Binding, Photocleavage, and Antioxidant Activity of Octahedral Ruthenium(II) Complexes

“…That in turn leads to final loss of cell integrity by disruption of the plasma membrane. [27] The assay of apoptosis induced by complex 3 was carried out with a staining method utilizing acridine orange (AO) and ethidium bromide (EB). [28] AO can pass through the cell membrane of living or early apoptotic cells, while staining by EB indicates loss of membrane integrity.…”