Herein, we describe and investigate biological activity of three octahedral ruthenium(II) complexes of the type [Ru(C∧N)(phen)2]+, RuL1-RuL3, containing a π-expansive cyclometalating substituted benzo[g]quinoxaline ligand (C∧N ligand) (phen = 1,10-phenanthroline). Compounds RuL1-RuL3 in cervical, melanoma, and colon human cancer cells exhibit high phototoxicity after irradiation with light (particularly blue), with the phototoxicity index reaching 100 for the complex RuL2 in most sensitive HCT116 cells. RuL2 accumulates in the cellular membranes. If irradiated, it induces lipid peroxidation, likely connected with photoinduced ROS generation. Oxidative damage to the fatty acids leads to the attenuation of the membranes, the activation of caspase 3, and the triggering of the apoptotic pathway, thus implementing membrane-localized photodynamic therapy. RuL2 is the first photoactive ruthenium-based complex capable of killing the hardly treatable colon cancer stem cells, a highly resilient subpopulation within a heterogeneous tumor mass, responsible for tumor recurrence and the metastatic progression of cancer.

• MeSH
• apoptóza účinky léků   MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• chinoxaliny * chemie   farmakologie   chemická syntéza   MeSH
• fotochemoterapie * MeSH
• fotosenzibilizující látky * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• komplexní sloučeniny * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky * účinky léků   patologie   MeSH
• nádory tračníku * farmakoterapie   patologie   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• ruthenium * chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Ru(II) "piano-stool" complexes belong to group of biologically active metallocomplexes with promising anticancer activity. In this study, we investigate the reaction mechanism of [(η(6)-benzene)Ru(II)(en)(H(2)O)](2+) (en = ethylenediamine) complex binding to DNA by hybrid QM/MM computational techniques. The reaction when the Ru(II) complex is coordinated on N7-guanine from major groove is explored. Two reaction pathways, direct binding to N7 position and two-step mechanism passing through O6 position, are considered. It was found that the reaction is exothermic and the direct binding process is preferred kinetically. In analogy to cisplatin, we also explored the possibility of intrastrand cross-link formation where the Ru(II) complex makes a bridge between two adjacent guanines. Two different pathways were found, leading to a final structure with released benzene ligand. This process is exothermic; however, one pathway is blocked by relatively high initial activation barrier. Geometries, energies, and electronic properties analyzed by atoms in molecules and natural population analysis methods are discussed.

• MeSH
• DNA chemie   MeSH
• ethylendiaminy chemie   MeSH
• kvantová teorie * MeSH
• molekulární struktura MeSH
• organokovové sloučeniny chemie   MeSH
• ruthenium chemie   MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The synthesis of the title 7-deazaadenine 2'-deoxyribonucleosides bearing bipyridine, phenanthroline or terpyridine ligands linked to position 7 via an acetylene or phenylene spacer is reported based on aqueous cross-coupling reactions of unprotected 7-iodo-7-deaza-2'-deoxyadenosine with ligand-functionalized acetylenes or boronic acids. The aqueous cross-coupling with acetylene or boronate building blocks containing the Ru(bpy)(3)-type of complex gave the corresponding Ru-containing nucleosides. Photophysical and electrochemical properties were studied and the most efficient type of complex was selected for future luminescent and redox labelling of DNA. The title nucleosides also showed some cytostatic and anti-HCV activities.

• MeSH
• 2,2'-dipyridyl chemie   MeSH
• antivirové látky farmakologie   MeSH
• financování organizované MeSH
• fotochemie MeSH
• Hepacivirus účinky léků   MeSH
• kultivované buňky MeSH
• lidé MeSH
• ligandy MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• organokovové sloučeniny chemie   MeSH
• oxidace-redukce MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• ruthenium chemie   MeSH
• screeningové testy protinádorových léčiv MeSH
• tubercidin analogy a deriváty   farmakologie   chemická syntéza   chemie   MeSH
• Check Tag
• lidé MeSH

A series of novel octahedral ruthenium(III) complexes involving 6-benzylaminopurine (L) derivatives as N-donor ligands has been prepared by the reaction of [(DMSO)(2)H][trans-RuCl(4)(DMSO)(2)] with the corresponding L derivative. The complexes 1-12 have the general compositions trans-[RuCl(4)(DMSO)(n-Cl-LH)]⋅xSol (1-3), trans-[RuCl(4)(DMSO)(n-Br-LH)]·xSol (4-6), trans-[RuCl(4)(DMSO)(n-OMe-LH)]·xSol (7-9) and trans-[RuCl(4)(DMSO)(n-OH-LH)]·xSol (10-12); n=2, 3, and 4, x=0-1.5; and Sol = H(2)O, DMSO, EtOH and/or (Me)(2)CO. The complexes have been thoroughly characterized by elemental analysis, UV-visible, FTIR, Raman, and EPR spectroscopy, ES+(positive ionization electrospray) mass spectrometry, thermal analysis, cyclic voltammetry, magnetic and conductivity measurements. The X-ray molecular structure of trans-[RuCl(4)(DMSO)(3-Br-LH)]⋅(Me)(2)CO (5) revealed the distorted octahedral coordination in the vicinity of the central atom, and also confirmed that the 3-Br-L ligand is present as the N3-protonated N7-H tautomer and is coordinated to Ru(III) through the N9 atom of the purine moiety. The tested complexes have been found to be in vitro non-cytotoxic against K562, G361, HOS and MCF7 human cancer cell lines with IC(50)>100μM in contrast to the moderate results regarding the antiradical activity with IC(50)≈10(-3)M. On the contrary, in vivo antitumor activity screening showed that the prepared Ru(III) complexes possess higher pro-apoptotic activity than NAMI-A. The reduction of Ru(III) to Ru(II) and Ru(II)-species formation in tumor tissues was confirmed by means of a simple method of detection and visualization of intracellular Ru(II) by fluorescence microscopy. The originality of this method is based on the preparation of a Ru(II)-bipyridine complex in situ.

• MeSH
• apoptóza účinky léků   MeSH
• dimethylsulfoxid analogy a deriváty   farmakologie   MeSH
• kinetin chemická syntéza   chemie   farmakologie   MeSH
• komplexní sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• krystalografie rentgenová MeSH
• leukemie L1210 farmakoterapie   patologie   MeSH
• lidé MeSH
• mitóza účinky léků   MeSH
• molekulární konformace MeSH
• myši inbrední DBA MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nekróza MeSH
• organokovové sloučeniny farmakologie   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• ruthenium MeSH
• screeningové testy protinádorových léčiv MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The new monofunctional Ru(II)-arene complex [(η⁶-arene)Ru(II)(en)Cl]+, where en = 1,2-diaminoethane and the arene is para-terphenyl (complex 1) exhibits promising cytotoxic effects in human tumor cells including those resistant to conventional cisplatin (J. Med. Chem.2008, 51, 5310). The present study is focused on the cellular pharmacology of 1 to elucidate more deeply the mechanisms underlying its antitumor effects. We have identified several cellular mechanisms induced by 1 in human ovarian carcinoma cells, including inhibition of DNA synthesis, overexpression and activation of p53, expression of proapoptotic proteins p21(WAF1) and Bax, G₀/G₁ arrest, and nuclear fragmentation as a result of apoptotic, and, to a much lower extent, also necrotic processes. Thus, 1 inhibits growth of the cancer cells through induction of apoptotic cell death and G₀/G₁ cell cycle arrest. Further investigations have shown that 1 induces apoptosis by regulating the expression of Bcl-2 family proteins. There were significant differences in cellular responses to the treatment with 1 and with conventional cisplatin, particularly in the kinetics and the extent of these responses. In addition, the distinct p53 activation profile of 1 compared with cisplatin provides an explanation for the activity of this ruthenium drug against cisplatin-resistant cells. Hence complex 1 may provide an alternative therapy in patients with acquired cisplatin resistance, particularly with respect to its very low mutagenicity and different mode of action compared to platinum antitumor drugs in clinical use.

• MeSH
• apoptóza účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• cisplatina chemie   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• ruthenium chemie   farmakologie   MeSH
• terfenylové sloučeniny chemie   farmakologie   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A series of ruthenium(II) and osmium(II) half-sandwich complexes was synthesized and characterized for its potential as a new class of anticancer agents. The complexes feature polycyclic aromatic hydrocarbon (PAH)-substituted Schiff bases and were rationally designed to combine the redox-modulating MoA of half-sandwich Ru, Rh, Os and Ir complexes, connected with their ability to induce the formation of various reactive oxygen species (ROS), with the ability of PAH-substituents to target and disrupt DNA. The complexes [Ru(η6-pcym)Cl(L)]PF6 (1-4) and [Os(η6-pcym)Cl(L)]PF6 (5-8) were stable in aqueous environments, in contrast to the rapid degradation observed for the co-studied rhodium(III) (9-12) and iridium(III) (13-16) [M(η5-Cp∗)Cl(L)]PF6 complexes; L = ethane-1,2-diamine-based Schiff bases (L1-L4) bearing two terminal PAH substituents 2-naphtyl (for L1), 9-anthracenyl (for L2), 9-phenanthrenyl (L3) or 1-pyrenyl (L4); pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), Cp∗ = pentamethylcyclopentadienyl. Biological testing demonstrated that 1-8 possess significant antiproliferative activity against various lung cancer cell lines, including those resistant to cisplatin, with Os(II) complex 5 showing the highest cytotoxicity. Treatment with these complexes led to the activation of stress-related gene pathways, including unconventional endoplasmic reticulum stress, apoptotic signalling, and mitochondrial membrane depolarization. Activation of p21/GADD45A pathway indicates DNA-damage response, as well. Notably, these complexes did not induce significant inflammatory responses, a notable advantage over cisplatin. The results highlight the potential of Ru and Os half-sandwich complexes as alternative metallodrugs, capable of overcoming platinum resistance and minimizing inflammatory side effects. This study suggests that these compounds could serve as a promising class of anticancer agents for future clinical development.

• MeSH
• komplexní sloučeniny * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• mitochondrie * účinky léků   metabolismus   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• organokovové sloučeniny * farmakologie   chemie   chemická syntéza   MeSH
• osmium * chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• ruthenium * chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• stres endoplazmatického retikula * účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

We report on the preparation and thorough characterization of cytotoxic half-sandwich complexes [Ru(η⁶-pcym)(bphen)(dca)]PF₆ (Ru-dca) and [Os(η⁶-pcym)(bphen)(dca)]PF₆ (Os-dca) containing dichloroacetate(1-) (dca) as the releasable O-donor ligand bearing its own cytotoxicity; pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline). Complexes Ru-dca and Os-dca hydrolyzed in the water-containing media, which led to the dca ligand release (supported by ¹H NMR and electrospray ionization mass spectra). Mass spectrometry studies revealed that complexes Ru-dca and Os-dca do not interact covalently with the model proteins cytochrome c and lysozyme. Both complexes exhibited slightly higher in vitro cytotoxicity (IC50 = 3.5 μM for Ru-dca, and 2.6 μM for Os-dca) against the A2780 human ovarian carcinoma cells than cisplatin (IC50 = 5.9 μM), while their toxicity on the healthy human hepatocytes was found to be IC50 = 19.1 μM for Ru-dca and IC50 = 19.7 μM for Os-dca. Despite comparable cytotoxicity of complexes Ru-dca and Os-dca, both the complexes modified the cell cycle, mitochondrial membrane potential, and mitochondrial cytochrome c release by a different way, as revealed by flow cytometry experiments. The obtained results point out the different mechanisms of action between the complexes.

• MeSH
• fenantroliny chemie   farmakologie   MeSH
• komplexní sloučeniny chemie   farmakologie   MeSH
• kyselina dichloroctová chemie   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• nádory vaječníků farmakoterapie   MeSH
• osmium chemie   MeSH
• proliferace buněk účinky léků   MeSH
• ruthenium chemie   MeSH
• uvolňování léčiv MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• aktivace lymfocytů MeSH
• hlavní histokompatibilní komplex MeSH
• interferon gama fyziologie   MeSH
• interleukin-2 farmakologie   MeSH
• myši MeSH
• T-lymfocyty - podskupiny imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH

CE using randomly highly sulfated α-, β-, and γ-CDs (S-α-CD, S-β-CD, S-γ-CD), sulfobutylether-β-CD (SBE-β-CD), single isomer (6-O-sulfo) α-, β-, and γ-CDs, and their derivatives as stereoselectors was applied to chiral analysis of polypyridyl complexes of [Ru(bpy)3 ](2+) , [Ru(phen)3 ](2+) , and [Fe(phen)3 ](2+) (bpy = 2,2'-bipyridine; phen = 1,10 phenanthroline). The best separations of Δ- and Λ-enantiomers of the these complexes with high resolution (up to R1,2 = 7.0) and short analysis times (10-20 min) were achieved in the BGE composed of 22 mM NaOH/35 mM H3 PO4 , pH 2.4, containing 1.5-6.0 mM S-α-CD or S-β-CD, or SBE-β-CD as chiral selectors. The developed method was applied to the assessment of enantiomeric purity of several samples of [Ru(bpy)3 ](2+) catalyst. CE experiments were performed in a homemade analyzer equipped with bare or hydroxypropylcellulose-coated fused-silica capillaries (total/effective length 40/29 cm, id/od 50/375 μm) and an UV absorption detector operating at 206 nm. In addition to chiral analysis, apparent binding constants of the complexes of [Ru(bpy)3 ](2+) , [Ru(phen)3 ](2+) , and [Fe(phen)3 ](2+) enantiomers with five sulfated CDs (S-α-CD, S-β-CD, S-γ-CD, SBE-β-CD, and 16Me-8S-γ-CD) were determined from the dependence of their effective electrophoretic mobilities on the concentration of the CDs in the BGE by nonlinear regression analysis. Calculated apparent binding constants of these complexes were found to be in the (1.10-4.66) × 10(3) L/mol range. Moreover, it was shown that at selected concentrations of some S-CDs and suppressed or very low electroosmotic flow, the exceptional enantioseparations with infinite resolution could be achieved.

• MeSH
• cyklodextriny chemie   MeSH
• elektroforéza kapilární metody   MeSH
• nelineární dynamika MeSH
• pyridiny analýza   chemie   MeSH
• ruthenium analýza   chemie   MeSH
• sírany chemie   MeSH
• stereoizomerie MeSH
• železnaté sloučeniny analýza   chemie   MeSH
• Publikační typ
• časopisecké články MeSH

The synthesis of the title 2'-deoxyadenosine derivatives bearing bipyridine, phenanthroline or terpyridine ligands and their corresponding RuII-complexes in position 8 linked via acetylene or phenylene tethers was accomplished through cross-coupling reactions. The Suzuki-Miyaura reactions of boronic acids or the Sonogashira reactions of terminal acetylene derivatives of oligopyridine ligands were performed either on protected 8-bromoadenosines in organic solvents or, more efficiently, directly on unprotected nucleosides in aqueous acetonitrile or DMF. Direct cross-coupling reactions of unprotected nucleosides with RuII-complexes or the oligopyridine-boronic acids or -acetylenes gave the Ru-labelled nucleosides in one step in fair to good yields. This method was also proven to be applicable for direct Ru-labelling of dATP. Terpyridine-containing 2'-deoxyadenosine exerted significant antiviral and cytostatic effects.

• MeSH
• antivirové látky chemická syntéza   chemie   toxicita   MeSH
• deoxyadenosiny chemická syntéza   chemie   toxicita   MeSH
• difrakce rentgenového záření MeSH
• financování organizované MeSH
• Hepacivirus účinky léků   MeSH
• ligandy MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• protinádorové látky chemická syntéza   chemie   toxicita   MeSH
• pyridiny chemie   MeSH
• reagencia zkříženě vázaná chemie   MeSH
• sloučeniny ruthenia chemie   MeSH