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Sava, Gianni; Capozzi, Ilaria; Clerici, K.; Gagliardi, G.; Alessio, Enzo; Mestroni, G.

doi:10.1023/a:1006521715400

Cited by 195 publications

(120 citation statements)

References 16 publications

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“…KP1019 is efficient in colorectal carcinoma models, while NAMI-A is an antimetastatic agent which can affect the motility of the cancer cells [12,13]. The mode of action and the intracellular targets of Ru(III) complexes are not exactly known.…”

Section: [Tetrachlorido(1h-imidazole)(dimethylsulfoxide-κs)ruthenate(mentioning

confidence: 99%

Solution equilibrium studies of anticancer ruthenium(II)-η6-p-cymene complexes of pyridinecarboxylic acids

et al. 2014

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Stoichiometry and stability of antitumor ruthenium(II)-η 6 -p-cymene complexes of picolinic acid and its 6-methyl and 6-carboxylic acid derivatives were determined by pHpotentiometry, 1 H NMR spectroscopy and UV/Vis spectrophotometry in aqueous solution in the presence or absence of coordinating chloride ions. The picolinates form exclusively monoligand complexes in which they can coordinate via the bidentate (O,N) mode and a chloride or a water molecule is found at the third binding site of the ruthenium(II)-η 6 -p-cymene moiety depending on the conditions. [Ru(η 6 -p-cymene)(L)(H 2 O/Cl)] species are predominant at physiological pH in all studied cases. Hydrolysis of the aqua complex or the chlorido/hydroxido co-ligand exchange results in the formation of the mixed-hydroxido species [Ru(η 6 -p-cymene)(L)(OH)] in the basic pH range. There is no indication for the decomposition of the mono-ligand complexes during 24 h in the ruthenium(II)-η 6 -pcymene−picolinic acid system between pH 3 and 11; however, a slight dissociation with a low reaction rate was found in the other two systems leading to the appearance of the dinuclear trihydroxido-bridged species [Ru 2 (η 6 -p-cymene) 2 (OH) 3 ] + and free ligands at pH > 10. The replacement of the chlorido by an aqua ligand in [Ru(η 6 -p-cymene)(L)Cl] was also monitored and equilibrium constants for the exchange process were determined.

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Section: [Tetrachlorido(1h-imidazole)(dimethylsulfoxide-κs)ruthenate(mentioning

confidence: 99%

Solution equilibrium studies of anticancer ruthenium(II)-η6-p-cymene complexes of pyridinecarboxylic acids

et al. 2014

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“…34 To date, two Ru(III) complexes, namely NAMI-A (4 in Figure 1) and NKP-1339 (5 in Figure 1) have entered into clinical trials. [36][37][38][39] Chemistry speaking, their mechanisms of action are comparable to that of cisplatin with the involvement of ligand exchange but any other detailed explanation about this is beyond of the scope of this Review. We send the interested readers to excellent Reviews.…”

Section: Introductionmentioning

confidence: 97%

Monomeric and dimeric coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes as anticancer drug candidates

2017

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Due to the increasing impact of cancer on worldwide mortality, more and more attention is being devoted to the investigation of novel anticancer strategies. Among these, chemotherapy plays a key role in fighting cancer. This explains the increasing engagement of both pharmaceutical industry and academia towards the discovery of new chemotherapeutic agents. Over the recent years, metal-based drugs have attracted much attention due to their atypical physico-chemical properties compared to organic molecules. After the approval of cisplatin as a chemotherapeutic agent in 1978, several types of metal-based drugs have been explored. Among them, Ru-based anticancer drug candidates have become a central subject in this research field. However, most of the Ru-based compounds investigated over the last two decades express their cytotoxicity with a mechanism of action involving, among others, a ligand-exchange mechanism. In this Review, we give a complete overview of a specific class of antiproliferative ruthenium complexes, namely coordinatively saturated and substitutionally inert Ru(II) polypyridyl complexes. This implies that the cytotoxicity observed comes from the entire complex and not from a ligand-exchange. In this Review, we are presenting monomeric and dimeric Ru(II) polypyridyl complexes, which have been found to be toxic to cancer cells. More specifically, the monomeric Ru(II) polypyridyl complexes are analysed considering their direct interaction or not with DNA as cause of cell death, while dimeric Ru(II) polypyridyl complexes, are classified according to their biological targets. Very importantly, the cellular targets of these complexes are discussed in detail. Indeed, several targets were identified and different mechanisms of action were suggested.

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“…Ruthenium compounds are currently considered the most likely candidates for the next generation of metal-based anticancer drugs [2,3]. Two representatives of this class of compounds have entered clinical trials so far: imidazolium trans-[tetrachlorido(dimethylsulfoxide)(1H-imidazole)ruthenate(III)] (NAMI-A) [4,5] and indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) [6][7][8] (see Chart 1 for structures). Only very moderate toxicities were observed in the case of KP1019 [6,7,9] whereas NAMI-A treatment was accompanied by painful blister formation at higher dosage, however that is actually higher than the advised dosage [10].…”

Section: Introductionmentioning

confidence: 99%

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

et al. 2012

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Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) and its Na + analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a non-covalent manner. In order to elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration−UV-vis spectrophotometry and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind into both sites with moderately to strong affinity (logK 1 ' = 5.3-5.8). No preference for either binding site was found and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event.

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Cited by 195 publications

References 16 publications

Solution equilibrium studies of anticancer ruthenium(II)-η6-p-cymene complexes of pyridinecarboxylic acids

Solution equilibrium studies of anticancer ruthenium(II)-η6-p-cymene complexes of pyridinecarboxylic acids

Monomeric and dimeric coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes as anticancer drug candidates

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

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