Effects of Hypoxia and Transferrin on Toxicity and DNA Binding ofRuthenium Antitumor Agents in Hela Cells

Frasca, Dominic R.; Ciampa, J.; Emerson, Jeffrey; Umans, Robert S.; Clarke, Michelle J.

doi:10.1155/mbd.1996.197

Cited by 67 publications

(59 citation statements)

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“…For the imidazole-containing analogue of KP1019, i.e., KP418, a stimulating effect of hypoxia on DNA binding, resulting in enhanced cytotoxicity, was observed in cell-culture experiments with HeLa cells. Under these conditions, increased Ru -DNA adduct formation was measured and may be explained by an increased concentration of Ru II species [85] [86]. The binding of KP1019 to 5'-GMP under the influence of glutathione was assayed by means of CE and was found to increase upon addition of 2 equiv.…”

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confidence: 99%

KP1019, A New Redox‐Active Anticancer Agent – Preclinical Development and Results of a Clinical Phase I Study in Tumor Patients

Hartinger

Jakupec

Zorbas‐Seifried

et al. 2008

Chemistry & Biodiversity

781

583

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The promising drug candidate indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) is the second Ru-based anticancer agent to enter clinical trials. In this review, which is an update of a paper from 2006 (Hartinger et al., J. Inorg. Biochem. 2006, 100, 891-904), the experimental evidence for the proposed mode of action of this coordination compound is discussed, including transport into the cell via the transferrin cycle and activation by reduction. The results of the early clinical development of KP1019 are summarized in which five out of six evaluated patients experienced disease stabilization with no severe side effects.

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confidence: 99%

KP1019, A New Redox‐Active Anticancer Agent – Preclinical Development and Results of a Clinical Phase I Study in Tumor Patients

Hartinger

Jakupec

Zorbas‐Seifried

et al. 2008

Chemistry & Biodiversity

781

583

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“…16) Transferrin normally transports Fe(III) in the blood but is only about one third occupied by Fe(III), and so there are vacant sites available for Ru(III) binding. Another important step in the mechanism of action of Ru(III) complexes is thought to be in vivo reduction to Ru(II), 17) which is kinetically more reactive than Ru(III).…”

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confidence: 99%

Synthesis, Anticancer and Antibacterial Activity of Some Novel Mononuclear Ru(II) Complexes

Mazumder

Gupta

Karki

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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The success of cisplatin and related platinum complexes as anticancer agents has stimulated a search for other active transition metal complexes, and ruthenium in particular has attracted the researchers.1) Metal complexes of ruthenium containing nitrogen and oxygen donor ligands are found to be effective catalysts for oxidation, reduction, hydrolysis and other organic transformation.2) The coordination environment around ruthenium plays the key role in stabilizing its different oxidation states and hence dictates the redox properties of the control atoms. (areneϭp-cymene, hexamethylbenzene and lϭcarbene or nitrogen containing heterocycles) have been tested for antibacterial and antifungal activity.The tris chelates of the ruthenium with bidentate ligands show intercalate properties with the DNA 13) and bind to Fe(III) sites of the proteins lactoferin and transferrin 14,15) and transferrin is thought to be responsible for the delivery of Ru(III) to cancer cells where it is taken up via receptor mediated endocytosis.16) Transferrin normally transports Fe(III) in the blood but is only about one third occupied by Fe(III), and so there are vacant sites available for Ru(III) binding. Another important step in the mechanism of action of Ru(III) complexes is thought to be in vivo reduction to Ru(II), 17) which is kinetically more reactive than Ru(III). Recently we have reported, N-alkyl and N-aryl substituted thiosemicarbazide complexes with Ru(bpy) 2 Cl 2 and greater antibacterial activity was found in the N-alkyl substituted complexes whereas N-aryl substituted exhibited more antitumor activity.18) In view of the above facts we have investigated the design of a novel range of Ru(II) complexes and the structural features as well as the contribution of the ligands that are responsible for antitumor and antibacterial activity. Results and DiscussionChemistry The ligands nmit (nmitϭN-methyl-isatin-3-thiosemicarbazone) and icpl (icplϭisatin-3-(4-chlorophenyl) thiosemicarbazone) were prepared by reacting Nmethylisatin and isatin with thiosemicarbazide and 4-chlorophenyl thiosemicarbazide in alcohol in presence of glacial acetic acid in 1 : 1 molar ratios respectively. Other ligands like r-tsc (r-tscϭ4-substituted thiosemicarbazides) were prepared according to the literature 19,20) with slight modification (Chart 1). All these ligands were confirmed for their purity by their melting point, elemental analysis and infrared spectra.Ruthenium metal complexes with the ligands nmit, icpl, aze (azeϭacetazolamide) and r-tsc were prepared by the reaction of a stoichiometric quantity of Ru(phen) 2 Cl 2 / Ru(bpy) 2 Cl 2 with the respective ligands in alcohol in presence of nitrogen (Chart 2). The completion of the reaction was monitored by TLC on silica gel.The structures of these ligands, especially nmit, icpl and rtsc in Fig. 1, show that in no case these ligands can exhibit tridentate behavior. There are very few cases in which the thiosemicarbazides act as monodentate ligands binding to the metal centre through the sulfur atom, th...

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“…There is evidence that DNA is the target for these complexes, which is similar to that of the well-established platinum drugs. [23][24][25][26] Many studies on their mode of action and on structure-activity relationship have been performed. However, many aspects of the tumorinhibiting action displayed by ruthenium complexes are still unknown.…”

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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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Effects of Hypoxia and Transferrin on Toxicity and DNA Binding ofRuthenium Antitumor Agents in Hela Cells

Cited by 67 publications

References 0 publications

KP1019, A New Redox‐Active Anticancer Agent – Preclinical Development and Results of a Clinical Phase I Study in Tumor Patients

KP1019, A New Redox‐Active Anticancer Agent – Preclinical Development and Results of a Clinical Phase I Study in Tumor Patients

Synthesis, Anticancer and Antibacterial Activity of Some Novel Mononuclear Ru(II) Complexes

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

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