Highly water-soluble ruthenium(II) terpyridine coordination compounds form stable adducts with blood-borne metal transporting proteins

Nišavić, Marija; Stoiljković, Milovan; Crnolatac, Ivo; Milošević, Maja; Rilak, Ana; Masnikosa, Romana

doi:10.1016/j.arabjc.2016.07.021

Cited by 22 publications

(14 citation statements)

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“…The synthesis of ruthenium(II) terpyridine complexes [Ru(Cl-tpy)(en)Cl][Cl] (abbreviated Ru - 1 ) and [Ru(Cl-tpy)(dach)Cl][Cl] (abbreviated Ru-2 ), their stability in aqueous solution, as well as their interaction with different biomolecules were thoroughly investigated [ 10 ]. It was demonstrated that these complexes can bind to HSA with moderate-to-strong affinity [ 11 ], which may be relevant given the fact that HSA is the leading protein responsible for drug transport and uptake, but is also thought to be crucial for antitumor activity of several ruthenium-based drug candidates [ 9 ]. Furthermore, it was reported that ruthenium(II) terpyridine complexes bind to DNA through intercalation by inserting the planar terpyridine ring between the DNA base pairs and through the covalent binding to guanine N7 [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo

et al. 2020

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Ruthenium complexes have attracted considerable interest as potential antitumor agents. Therefore, antitumor activity and systemic toxicity of ruthenium(II) terpyridine complexes were evaluated in heterotopic mouse colon carcinoma. In the present study, cytotoxic effects of recently synthesized ruthenium(II) terpyridine complexes [Ru(Cl-tpy)(en)Cl][Cl] (en = ethylenediamine, tpy = terpyridine, Ru-1) and [Ru(Cl-tpy)(dach)Cl][Cl] (dach = 1,2-diaminocyclohexane, Ru-2) towards human and murine colon carcinoma cells were tested in vitro and in vivo and compared with oxaliplatin, the most commonly used chemotherapeutic agent against colorectal carcinoma. Ruthenium(II) complexes showed moderate cytotoxicity with IC50 values ranging between 19.1 to 167.3 μM against two human, HCT116 and SW480, and one mouse colon carcinoma cell line, CT26. Both ruthenium(II) terpyridine complexes exerted a moderate apoptotic effect in colon carcinoma cells, but induced significant necrotic death. Additionally, both complexes induced cell cycle disturbances, but these effects were specific for the cell line. Further, Ru-1 significantly reduced the growth of primary heterotopic tumor in mice, similarly to oxaliplatin. Renal damage in Ru-1 treated mice was lower in comparison with oxaliplatin treated mice, as evaluated by serum levels of urea and creatinine and histological evaluation, but Ru-1 induced higher liver damage than oxaliplatin, evaluated by the serum levels of alanine aminotransferase. Additionally, the interaction of these ruthenium(II) terpyridine complexes with the tripeptide glutathione (GSH) was investigated by proton nuclear magnetic resonance (1H NMR) spectroscopy. All reactions led to the formation of monofunctional thiolate adducts [Ru(Cl-tpy)(en)GS-S] (3) and [Ru(Cl-tpy)(dach)GS-S] (4). Our data highlight the significant cytotoxic activity of [Ru(Cl-tpy)(en)Cl][Cl] against human and mouse colon carcinoma cells, as well as in vivo antitumor activity in CT26 tumor-bearing mice similar to standard chemotherapeutic oxaliplatin, accompanied with lower nephrotoxicity in comparison with oxaliplatin.

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Section: Introductionmentioning

confidence: 99%

Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo

et al. 2020

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“…Based on the obtained MS results and spatial localization of the identified target sequences, it can be concluded that there are three HSA regions for the binding of the tested Ru compounds (Fig. S10) previously determined average number of bound complex molecules per protein (seven for compound 1, nine for 2 and two for complex 3) was taken into account 29 . The illustration of binding sites for each complex chloro-, aqua-and hydroxo-form is shown in Fig.…”

Section: Docking Studiesmentioning

confidence: 92%

Positive and negative nano-electrospray mass spectrometry of ruthenated serum albumin supported by docking studies: an integrated approach towards defining metallodrug binding sites on proteins

et al. 2018

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Binding of three ruthenium(ii) compounds of general formula mer-[Ru(L3)(N-N)X][Y] (where L3 = 4'-chloro-2,2':6',2''-terpyridine (Cl-tpy); N-N = 1,2-diaminoethane (en), 1,2-diaminocyclohexane (dach) or 2,2'-bipyridine (bipy); X = Cl; Y = Cl) to human serum albumin (HSA) has been investigated by nano-LC/nano-ESI MS and docking studies. A bottom-up proteomics approach has been applied for the structural characterization of metallated proteins and the data were analyzed in both the positive and negative ion mode. The negative ion mode was achieved after the post-column addition of an isopropanol solution of formaldehyde that enabled sample ionization at micro-flow rates. The negative ion mode MS has been proved to be beneficial for the analysis of binding sites on ruthenated protein in terms of ion charge reduction and consequent simplification of target sequence identification based on isotopic differences between ruthenated and non-ruthenated peptides. Moreover, the negative ion mode ESI MS shows the advantage of singly charged ion formation and, unlike MALDI MS, it does not cause complete ligand fragmentation, merging the benefits of each method into a single experiment. Six target sequences were identified for the binding of en and dach compounds, and four sequences for the binding of bipy. All compounds have been found to bind histidine and one aspartate residue. Docking studies showed that the identified sequences are the constituents of five distinct binding sites for en and dach, or two sites for the bipy complex. The selection of binding sites seems to be dependent on the chelate ligand and the form of the complex prior or after hydrolysis of the leaving chloride ligand.

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“…Without any postprocessing, the printed constructs were directly used for cultures, where the sacrificial gelatin and remnant Ru/SPS in the shell were easily dissolved upon incubation at 37 °C for 20 min. [63,64,70] Cell Viability and Proliferation Assay: To conduct a viability test, the 3D embedded cells and printed constructs were evaluated by staining with a LIVE/DEAD Viability/Cytotoxicity Kit (Thermo Fisher Scientific, USA) following the manufacturer's instructions. To evaluate the proliferation of the printed cells, the metabolic activity of the cells was measured using a Cell Counting Kit-8 (CCK-8, Dojindo, Japan) following the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

“…[61] In addition, the high molar extinction coefficient of ruthenium allows remarkably faster and more stable reactions even at low concentrations. [62] Finally, Ru/SPS is highly watersoluble, [63,64] which means that remnant initiators can be dissolved into a physiological solution, such as the culture medium.…”

Section: One-step Fabrication Of a Tubular Structure With A Hollow Lumen Using The Colon Dersmentioning

confidence: 99%

A Bioprinted Tubular Intestine Model Using a Colon‐Specific Extracellular Matrix Bioink

Han

Park

Choi

et al. 2021

Adv Healthcare Materials

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Tremendous advances have been made toward accurate recapitulation of the human intestinal system in vitro to understand its developmental process, and disease progression. However, current in vitro models are often confined to 2D or 2.5D microarchitectures, which is difficult to mimic the systemic level of complexity of the native tissue. To overcome this problem, physiologically relevant intestinal models are developed with a 3D hollow tubular structure using 3D bioprinting strategy. A tissue-specific biomaterial, colon-derived decellularized extracellular matrix (Colon dECM) is developed and it provides significant maturation-guiding potential to human intestinal cells. To fabricate a perfusable tubular model, a simultaneous printing process of multiple materials through concentrically assembled nozzles is developed and a light-activated Colon dECM bioink is employed by supplementing with ruthenium/sodium persulfate as a photoinitiator. The bioprinted intestinal tissue models show spontaneous 3D morphogenesis of the human intestinal epithelium without any external stimuli. In consequence, the printed cells form multicellular aggregates and cysts and then differentiate into several types of enterocytes, building junctional networks. This system can serve as a platform to evaluate the effects of potential drug-induced toxicity on the human intestinal tissue and create a coculture model with commensal microbes and immune cells for future therapeutics.

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Highly water-soluble ruthenium(II) terpyridine coordination compounds form stable adducts with blood-borne metal transporting proteins

Cited by 22 publications

References 62 publications

Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo

Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo

Positive and negative nano-electrospray mass spectrometry of ruthenated serum albumin supported by docking studies: an integrated approach towards defining metallodrug binding sites on proteins

A Bioprinted Tubular Intestine Model Using a Colon‐Specific Extracellular Matrix Bioink

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