New Uses for Old Drugs: Attempts to Convert Quinolone Antibacterials into Potential Anticancer Agents Containing Ruthenium

Kljun, Jakob; Bratsos, Ioannis; Alessio, Enzo; Psomas, George; Repnik, Urška; Butinar, Miha; Turk, Boris; Turel, Iztok

doi:10.1021/ic401220x

Cited by 107 publications

(91 citation statements)

References 73 publications

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“…42 Ligand-exchange reaction on the ruthenium ion caused by DMSO tends to reach an equilibrium, in which, according to Turel, 10−50% of the ligand may remain free. 12 However, in aqueous solutions, exchange of the anionic (halogenide) ligands is considered to be a part of the complex activation. The newly formed complex has enhanced reactivity with nucleophilic targets in the cells.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…10,11 Recent studies on ruthenium complexes with the quinolone showed an increased toxicity against selected cancer cell lines. 12,13 The synthesis of two new ruthenium(II)-cymene complexes has been reported here along with their cytotoxic activities against five human neoplastic cell lines. One complex was prepared with a new ligand, 1-(7-chloroquinolin-4-yl)thiourea (L1), and the other with 3-(4,5-dihydro-1H-imidazol-2-yl)-pyridine hydrochloride (L2).…”

Section: ■ Introductionmentioning

confidence: 99%

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Strong in Vitro Cytotoxic Potential of New Ruthenium–Cymene Complexes

et al. 2015

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Two p-cymenerutheniumchlorido complexes with thiourea derivative of 7-chloroquinoline (C1) and pyridine-3-imidazole (C2) were synthesized starting from [(η 6 -p-cymene)RuCl 2 ] 2 and corresponding ligands. The structures of complexes were determined with elemental analysis and IR, ESIMS, 1 H and 13 C{ 1 H} NMR, and 2D 1 H− 15 N correlation NMR spectroscopy. Cytotoxic activities examined by the MTT assay were performed in five human neoplastic cell lines (HeLa, K562, A549, MDA-MB-231, EA.hy926) and one nontumor human fetal lung fibroblast cell line (MRC-5). Tested complexes exhibited low micromolar activities with IC 50 in the range 11.03−56.45 μM, while ligands L1 and L2 were significantly less active. Complex C1 showed cytoselective activity toward the K562 cell line (IC 50 = 11.03 ± 1.39 μM) and was 3 times less active against the nontumor MRC-5 cell line. Flow cytometry analysis indicated that complexes C1 and C2 after 24 h treatment caused a concentration-dependent increase of the apoptotic sub-G1 fraction (up to 18.4%), comparable to cis-diamminedichloridoplatinum(II) (cisplatin, CDDP), although without other substantial alterations of the cell cycle. A drug-accumulation and DNA-binding study performed by ICP-MS in the K562 cell line revealed that complex C1 had a high intracellular uptake (1.38 μg Ru/10 6 cells), which significantly exceeded the intracellular uptake levels of CDDP (0.29 μg Pt/10 6 cells) and C2 (0.08 μg Ru/10 6 cells). However, both ruthenium complexes C1 and C2 bind to cellular DNA less efficiently in comparison to CDDP. The structure−activity relationship clearly suggested that introduction of a 7-chloroquinoline moiety in the ruthenium(II)-p-cymene complex significantly contributed to the intracellular uptake of C1 and higher cytotoxicity and cytoselectivity.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Strong in Vitro Cytotoxic Potential of New Ruthenium–Cymene Complexes

et al. 2015

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“…This strategy raises the interesting question of how metal binding will modulate the biological activity of the drug and if synergistic effects can be achieved this way. 20,21 Particularly promising in this context are azole-based drugs, which have been explored in the context of antifungal chemotherapy for a number of decades. 22−24 Due to the presence of free nitrogen donor centers, these compounds can easily be coodinated to a wide range of metal-coligand fragments.…”

Section: ■ Introductionmentioning

confidence: 99%

Antibacterial and Antiparasitic Activity of Manganese(I) Tricarbonyl Complexes with Ketoconazole, Miconazole, and Clotrimazole Ligands

et al. 2015

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Five manganese(I) tricarbonyl complexes of the general formula [Mn(CO) 3 (bpy R,R )(azole)]PF 6 with R = H, COOCH 3 , and azole = ketoconazole (ktz), miconazole (mcz), and clotrimazole (ctz) were synthesized and fully charaterized, including X-ray structure analysis for the ctz compound. The antibacterial activity on a panel of eight Gram-positive and Gram-negative bacterial strains was determined. While there was no effect on the latter microorganisms, the ctz complex showed submicromolar activity on Staphylococcus aureus and S. epidermidis with MIC values of 0.625 μM. Antiparasitic activity was investigated on Leishmania major and Trypanosoma brucei. Coordination of the organic azole drugs to the Mn(CO) 3 moiety led to complexes with low micromolar IC 50 values, but their potential for antileishmanial therapy is low due to comparable toxicity on mammalian cell lines 293T and J774.1. In contrast, the antitrypanosomal activity is much more promising, and the most potent compound incorparting the ktz ligand has an IC 50 value on T. brucei of 0.7 μM with selectivity on parasitic over mammalian cells as expressed by a selectivity index above 10. These results demonstrate that metal coordination of established drugs can significantly improve their biological activity and expand their range of medicinal applications.

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“…KP1019 is a substance that has a potential to be used against many tumours that are resistant to cisplatin [11]. Several other ruthenium complexes were prepared and tested for biological activity and our focus in last years were ruthenium complexes of antibacterial agents quinolones [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%