Synthesis, interaction with double-helical DNA and biological activity of the water soluble complex cis-dichloro-1,2-propylenediamine-N,N,N′,N′-tetraacetato ruthenium (III) (RAP)

Chemotherapeutic agents play an important role in cancer treatment mostly due their systemic action on human organism allowing access to liquid tumors and even metastases. Among these drugs, ruthenium compounds have been showing promising results to treat tumors and represent an important development of new antitumor therapy. This study presents the evaluation of cis-(dichloro)tetraammineruthenium(III) chloride, cis-[RuCl(2)(NH(3))(4)]Cl, genotoxic effects using human peripheral blood lymphocytes cultured in vitro. Mitotic index (MI), chromosome aberrations (CA), and DNA damage using the comet assay were analyzed. MI in human peripheral blood lymphocyte cultures treated with 1, 10, 100, and 1,000 microg mL(-1) cis-[RuCl(2)(NH(3))(4)]Cl were 5.9%, 4.6%, 3.9%, and 0%, respectively. Doxorubicin chloridate was used as the positive control. CA derived from 1, 10, and 100 microg mL(-1) concentrations were defined as spontaneous when compared with the negative control, and at the concentration of 1,000 microg mL(-1), the cell cycle was inhibited (IM = 0%). Results obtained for the comet assay using cis-[RuCl(2)(NH(3))(4)]Cl suggest that this compound has no genotoxic activity against cultured human peripheral blood lymphocytes.

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“…The rearragement of lymphocytes in peripheral blood may be an indicator of increased risk of secondary neoplasy [44][45][46][47][48].…”

Section: Discussionmentioning

confidence: 99%

Mutagenic and Genotoxic Effects of cis-(Dichloro)tetraammineruthenium(III) Chloride on Human Peripheral Blood Lymphocytes

Ribeiro

Silva

Pereira

et al. 2009

Biol Trace Elem Res

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“…[5][6][7][8][9][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][12][13][14][15][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.…”

mentioning

confidence: 99%

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

Matsui

Sugiyama

Nakai

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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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...

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“…Several studies have shown that ruthenium complexes induce DNA damage in the tumour cells, mainly by intercalant effects (Kapitza et al 2005a;Vilaplana et al 2006). A previous report indicated that cis-[RuCl 2 (NH 3 ) 4 ]Cl induces internucleosomal DNA J.…”

Section: Discussionmentioning

confidence: 99%

The ruthenium complex cis-(dichloro)tetrammineruthenium(III) chloride induces apoptosis and damages DNA in murine sarcoma 180 cells

et al. 2010

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Ruthenium (III) complexes are increasingly attracting the interest of researchers due to their promising pharmacological properties. Recently, we reported that the cis-(dichloro)tetrammineruthenium (III) chloride compound has cytotoxic effects on murine sarcoma 180 (S-180) cells. In an effort to understand the mechanism responsible for their cytotoxicity, study we investigated the genotoxicity, cell cycle distribution and induction of apoptosis caused by cis- (dichloro) tetrammineruthenium (III) chloride in S-180 tumour cells. cis-(dichloro) tetrammineruthenium (III) chloride treatment induced significant DNA damage in S-180 cells, as detected by the alkaline comet assay. In the cell cycle analysis, cis-(dichloro) tetrammineruthenium (III) chloride caused an increase in the number of cells in G1 phase, accompanied by a decrease in the S and G2 phases after 24 h of treatment. In contrast, the cell cycle distribution of S-180 cells treated with cis-(dichloro) tetrammineruthenium (III) chloride for 48 h showed a concentration-dependent increase in the sub-G1 phase (indicating apoptosis), with a corresponding decrease in cells in the G1, S and G2 phases. In addition, cis-(dichloro) tetrammineruthenium(III) chloride treatment induced apoptosis in a time-dependent manner,as observed by the increased numbers of annexin V-positive cells. Taken together, these findings strongly demonstrate that DNA damage, cell cycle changes and apoptosis may correlate with the cytotoxic effects of cis-(dichloro) tetrammineruthenium (III) chloride on S-180 cells.

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Synthesis, interaction with double-helical DNA and biological activity of the water soluble complex cis-dichloro-1,2-propylenediamine-N,N,N′,N′-tetraacetato ruthenium (III) (RAP)

Cited by 18 publications

References 40 publications

Mutagenic and Genotoxic Effects of cis-(Dichloro)tetraammineruthenium(III) Chloride on Human Peripheral Blood Lymphocytes

Mutagenic and Genotoxic Effects of cis-(Dichloro)tetraammineruthenium(III) Chloride on Human Peripheral Blood Lymphocytes

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

The ruthenium complex cis-(dichloro)tetrammineruthenium(III) chloride induces apoptosis and damages DNA in murine sarcoma 180 cells

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