DNA Interaction and Cytotoxicity of Cyclometalated Ruthenium(II) Complexes as Potential Anticancer Drugs

Abstract

To evaluate the anticancer activity of the cyclometalated ruthenium(II) complexes [Ru(bpy) 2 (C^N)]Cl, we have studied the interaction of these complexes using calf thymus DNA (CT-DNA) and cytotoxicity assays with two tumor (L1210 and HeLa) and a non-tumor (BALB/3T3 clone A31) cell lines. It is suggested that the complexes act as intercalators and/or DNA minor groove binders. Moreover, the complexes display favorable cytotoxicity activities with L1210 and HeLa, which in all cases were significantly more favorable than cisplatin. In contrast, the complexes exhibit appreciably lower cytotoxicity toward BALB/3T3 clone A31.Key words cyclometalated ruthenium(II) complex; anticancer drug; cytotoxicity; oxidative DNA cleavage; lipophilicityThe discovery of cisplatin (cis-diamminedichloridoplatinum(II)) by Rosenberg was one of the most significant events for cancer chemotherapy.1) However, the use of cisplatin is restricted by its high toxicity, which leads to undesirable side effects and incidents of drug resistance. With the aim of overcoming these limitations, new platinum-based and non-platinum anticancer drugs are under development. A relatively new line of investigation focuses on ruthenium chemistry in an alternative metallopharmaceutical approach to platinum.2,3) The higher coordination number of ruthenium compared with platinum provides additional coordination sites, which can potentially be used to fine-tune the properties of the complex, for example, by influencing the way the complex interacts with DNA. 4)It is well accepted that ruthenium complexes can display anticancer effects with a fairly high selectivity, the lethality of the tumor cells being higher than that of the normal cells.5-10) Several ruthenium complexes that display an activity comparable to that of cisplatin have been described, and in some cases activities are even better.11-16) Pfeffer and colleagues 17,18) and Chao and colleagues 19,20) have found that some cyclometalated ruthenium(II) complexes are good candidates for becoming anticancer drugs. A cyclometalated ruthenium fragment with a metal-carbon σ bond is a crucial element for a potential anticancer drug. The ruthenium-carbon bond is known to lower the redox potential of ruthenium(III/II) couple dramatically, so that cyclometalated ruthenium(II) complexes may serve as good catalysts for the generation of hydroxyl radicals by virtue of the Fenton-like reaction. In addition, they have good lipophilicity that allows their entries into the cells. 18,20) From two features these cyclometalated ruthenium(II) complexes may lead to excellent anticancer drugs because many cancer cells possess low levels of catalase activity. 21)In the present study, we have synthesized the cyclometalated ruthenium(II) complexes as shown in Fig. 1, [Ru(bpy) 2 (C^N)] Cl, where bpy is 2,2′-bipyridine and C^N is the deprotonated cyclometalating ligand (2-phenylpyridine (phpy), 2-(4-methylphenyl) pyridine (mphpy), or diphenyldiazene (dphdaz)). To evaluate the anticancer activity of these complexes physicochemical p...

An overview of recent advances in duplex DNA recognition by small molecules

“…CD and UV experiments revealed DHA analogs bind to DNA via intercalation and fluorine analogs act as intercalator as well as minor groove binder. Nakabayashi et al reported three cyclometalated ruthenium(II) complexes [Ru(bpy) 2 (C^N)]Cl 104 – 106 in order to study their ct-DNA binding affinity and cytotoxicity against two tumor (L1210 and HeLa) and a non-tumor (BALB/3T3 clone A31) cell lines [ 186 ]. Conjugates 104–106 primarily act as intercalators and/or minor groove binders.…”

Design and Syntheses of Novel Fluoroporphyrin–Anthraquinone Complexes as Antitumor Agents

“…Billions of dollars are spent annually on research in order to cure or improve the life-standards of the cancer patients. [1][2][3] The traditional cancer treatments, including surgery, radiation therapy and chemotherapy, result in serious adverse effects caused by the loss of the functions of normal organs. 1) Photodynamic therapy (PDT) is a form of phototherapy using nontoxic light-sensitive compounds that are exposed selectively to light, whereupon they become toxic to targeted malignant and other diseased cells.…”