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

Metastatic cancer remains a formidable challenge in anticancer therapy. Despite efforts to develop effective antimetastasis drugs over the past half-century, currently approved treatments fall short of expectations. This report highlights the promising antiproliferative activity of a ruthenium-based therapeutic agent, namely dichlorido(p-cymene)[2-amino-4-(pyridin-3-yl)-4H-benzo[h]-chromene-3-carbonitrile]ruthenium(II) (complex 1) against metastatic cell lines. Complex 1 shows significant efficacy in metastatic LoVo and Du-145 cell lines at nanomolar concentrations, being markedly more active than clinically used anticancer cisplatin. Studies on the MDA-MB-231 cell line, which displays invasive characteristics, demonstrated that 1 significantly reduces cell invasion. This efficacy was confirmed by its impact on matrix metalloproteinase production in MDA-MB-231 cells. Given that cell migration drives cancer invasion and metastasis, complex 1's effect on MDA-MB-231 cell migration was evaluated via wound healing assay and vimentin network analysis. Results indicated a strong reduction in migration. A re-adhesion assay further demonstrated that 1 significantly lowers the re-adhesion ability of MDA-MB-231 cells compared to cisplatin. To better simulate the human body environment, a 3D spheroid invasion assay was used. This method showed that 1 effectively inhibits tumor spheroids from infiltrating the surrounding extracellular matrix. This study underscores the potential of (arene)ruthenium(II) complexes with naphthopyran ligands as potent antimetastatic agents for chemotherapy.

• MeSH
• buněčná adheze účinky léků   MeSH
• komplexní sloučeniny * farmakologie   chemie   terapeutické užití   MeSH
• lidé MeSH
• metastázy nádorů prevence a kontrola   farmakoterapie   MeSH
• nádorové buněčné linie MeSH
• pohyb buněk * účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   terapeutické užití   MeSH
• ruthenium * chemie   farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The carbosilane metallodendrimer G1-[[NCPh(o-N)Ru(η6- p-cymene)Cl]Cl]4 (CRD13), based on an arene Ru(II) complex coordinated to imino-pyridine surface groups, has been conjugated with anti-cancer drugs. Ruthenium in the positively-charged dendrimer structure allows this nanoparticle to be considered as an anticancer drug carrier, made more efficient because ruthenium has anticancer properties. The ability of CRD13 to form complexes with Doxorubicin (DOX), 5-Fluorouracil (5-Fu), and Methotrexate (MTX) has been evaluated using zeta potential measurement, transmission electron microscopy (TEM) and computer simulation. The results show that it forms stable nanocomplexes with all those drugs, enhancing their effectiveness against MDA-MB-231 cancer cells. In vivo tests indicate that the CRD13/DOX system caused a decrease of tumor weight in mice with triple negative breast cancer. However, the tumors were most visibly reduced when naked dendrimers were injected.

• MeSH
• komplexní sloučeniny * chemie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nosiče léků MeSH
• počítačová simulace MeSH
• protinádorové látky * chemie   MeSH
• ruthenium * chemie   MeSH
• screeningové testy protinádorových léčiv MeSH
• triple-negativní karcinom prsu * farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

While ruthenium arene complexes have been widely investigated for their medicinal potential, studies on homologous compounds containing a tridentate tris(1-pyrazolyl)methane ligand are almost absent in the literature. Ruthenium(II) complex 1 was obtained by a modified reported procedure; then, the reactions with a series of organic molecules (L) in boiling alcohol afforded novel complexes 2-9 in 77-99% yields. Products 2-9 were fully structurally characterized. They are appreciably soluble in water, where they undergo partial chloride/water exchange. The antiproliferative activity was determined using a panel of human cancer cell lines and a noncancerous one, evidencing promising potency of 1, 7, and 8 and significant selectivity toward cancer cells. The tested compounds effectively accumulate in cancer cells, and mitochondria represent a significant target of biological action. Most notably, data provide convincing evidence that the mechanism of biological action is mediated by the inhibiting of mitochondrial calcium intake.

• MeSH
• homeostáza MeSH
• komplexní sloučeniny * farmakologie   MeSH
• lidé MeSH
• mitochondrie MeSH
• nádorové buněčné linie MeSH
• nádory * farmakoterapie   MeSH
• protinádorové látky * farmakologie   terapeutické užití   MeSH
• ruthenium * farmakologie   MeSH
• vápník MeSH
• voda MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Glycoconjugation is a powerful tool to improve the anticancer activity of metal complexes. Herein, we modified commercial arylphosphanes with carbohydrate-derived fragments for the preparation of novel glycoconjugated ruthenium(II) p-cymene complexes. Specifically, d-galactal and d-allal-derived vinyl epoxides (VEβ and VEα) were coupled with (2-hydroxyphenyl)diphenylphosphane, affording the 2,3-unsaturated glycophosphanes 1β and 1α. Ligand exchange with [Ru(C2O4)(η6-p-cymene)(H2O)] gave the glycoconjugated complexes Ru1β and Ru1α which were subsequently dihydroxylated with OsO4/N-methylmorpholine N-oxide to Ru2β and Ru2α containing O-benzyl d-mannose and d-gulose units respectively. Besides, aminoethyl tetra-O-acetyl-β-d-glucopyranoside was condensed with borane-protected (4-diphenylphosphanyl)benzoic acid by HATU/DIPEA under MW heating, to afford the amide 3∙BH3. Zemplén deacylation with MeONa/MeOH gave the deprotected d-glucopyranoside derivative 4∙BH3. The glycoconjugated phosphane complexes Ru3 and Ru4 were obtained by reaction of the phosphane-boranes 3∙BH3 and 4∙BH3 with [Ru(C2O4)(η6-p-cymene)(H2O)]. The employed synthetic strategies were devised to circumvent unwanted phosphine oxidation. The compounds were purified by silica chromatography, isolated in high yield and purity and characterized by analytical and spectroscopic (IR and multinuclear NMR) techniques. The behaviour of the six glycoconjugated Ru complexes in aqueous solutions was assessed by NMR and MS measurements. All compounds were screened for their in vitro cytotoxicity against A2780/A2780R human ovarian and MCF7 breast cancer cell lines, revealing a significant cytotoxicity for complexes containing the 2,3-unsaturated glycosyl unit (Ru1β, Ru1α). Additional studies on five other human cancer cells, as well as time-dependent toxicity and cell-uptake analyses on ovarian cancer cells, confirmed the prominent activity of these two compounds - higher than cisplatin - and the better performance of the β anomer. However, Ru1β, Ru1α did not show preferential activity against cancer cells with respect to fetal lung fibroblast and human embryonic kidney cells as models of normal cells. The effects of the two ruthenium glycoconjugated compounds in A2780 ovarian cancer cells were further investigated by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential. The latter is a relevant factor in the mechanism of action of the highly cytotoxic Ru1β, inducing cell death by apoptosis.

• MeSH
• fosfiny MeSH
• komplexní sloučeniny * chemie   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků * MeSH
• protinádorové látky * chemie   MeSH
• ruthenium * chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-occurs with DON as its glucosylated form and is another emerging food safety issue in recent years. However, the toxicity of D3G is not fully understood compared to DON, especially in emetic potency. The goals of this research were to (1) compare emetic effects to D3G by oral and intraperitoneal (IP) routes and relate emetic effects to brain-gut peptides glucose-dependent insulinotropic polypeptide (GIP) and substance P (SP) in mink; (2) determine the roles of calcium-sensing receptor (CaSR) and transient receptor potential (TRP) channel in D3G's emetic effect. Both oral and IP exposure to D3G elicited marked emetic events. This emetic response corresponded to an elevation of GIP and SP. Blocking the GIP receptor (GIPR) diminished emetic response induction by GIP and D3G. The neurokinin 1 receptor (NK-1R) inhibitor Emend® restrained the induction of emesis by SP and D3G. Importantly, CaSR antagonist NPS-2143 or TRP channel antagonist ruthenium red dose-dependently inhibited both D3G-induced emesis and brain-gut peptides GIP and SP release; cotreatment with both antagonists additively suppressed both emetic and brain-gut peptide responses to D3G. To summarize, our findings demonstrate that activation of CaSR and TRP channels contributes to D3G-induced emesis by mediating brain-gut peptide exocytosis in mink.

• MeSH
• emetika * toxicita   MeSH
• glukosa MeSH
• glukosidy MeSH
• norek MeSH
• receptory gastrointestinálních hormonů MeSH
• receptory spřažené s G-proteiny MeSH
• substance P MeSH
• trichotheceny * chemie   toxicita   MeSH
• zvířata MeSH
• zvracení chemicky indukované   MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Four bipyridine-type ligands variably derivatized with two bioactive groups (taken from ethacrynic acid, flurbiprofen, biotin, and benzylpenicillin) were prepared via sequential esterification steps from commercial 2,2'-bipyridine-4,4'-dicarboxylic acid and subsequently coordinated to ruthenium(II) p-cymene and iridium(III) pentamethylcyclopentadienyl scaffolds. The resulting complexes were isolated as nitrate salts in high yields and fully characterized by analytical and spectroscopic methods. NMR and MS studies in aqueous solution and in cell culture medium highlighted a substantial stability of ligand coordination and a slow release of the bioactive fragments in the latter case. The complexes were assessed for their antiproliferative activity on four cancer cell lines, showing cytotoxicity to the low micromolar level (equipotent with cisplatin). Additional biological experiments revealed a multimodal mechanism of action of the investigated compounds, involving DNA metalation and enzyme inhibition. Synergic effects provided by specific combinations of metal and bioactive fragments were identified, pointing toward an optimal ethacrynic acid/flurbiprofen combination for both Ru(II) and Ir(III) complexes.

• MeSH
• iridium chemie   farmakologie   MeSH
• komplexní sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• nádorové buňky kultivované MeSH
• poškození DNA MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• pyridiny chemie   farmakologie   MeSH
• ruthenium chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Cílem terapie nitroočního melanomu je dosáhnout lokální kontroly nad tumorem a snížit riziko generalizace onemocnění, zachovat oční bulbus, případně i zrakovou funkci oka. Volba terapeutického postupu vyžaduje komplexní pohled a individuální přístup. Zohledňuje se lokální nález, věk a fyzická i psychická kondice pacienta. Zlatým standardem v léčbě uveálního melanomu je radioterapie. Vlastní účinek záření vzniká absorpcí energie ionizujícího záření, efekt záření na buňku se projeví přímým zánikem buňky (deplecí), nebo změnou cytogenetické informace buňky (mutací). Při brachyterapii se využívají sklerální aplikátory s radionuklidem – v Evropě dominují rutheniové aplikátory (Ru-106), v USA jodové aplikátory (I-125). Při zevní radioterapii je zdroj ionizujícího záření mimo tělo pacienta. Využívá se technika jak stereotaktické radiochirurgie (tj. jednorázové ozáření tumoru), tak frakcionované stereotaktické radioterapie. V ČR je léčba prováděna pomocí Leksellova gama nože nebo kybernetického nože CyberKnife, ve světě dominuje protonová terapie. Je nutné počítat s rozvojem často závažných poradiačních komplikací (radiační retinopatie, neuropatie, neovaskulární glaukom, toxic tumor syndrom atd.). Chirurgická terapie zahrnuje celou řadu invazivních zákroků. U melanomu duhovky se provádí iridektomie. Anteriorně uložené choroidální melanomy a/nebo melanomy řasnatého tělesa mohou být řešeny transsklerální resekcí (exoresekcí). U choroidálních melanomů uložených posteriorně se využívá kombinace zevního ozáření tumoru s endoresekcí pomocí pars plana vitrektomie. Enukleace je metoda volby u pokročilých tumorů, které nelze účinně ozářit. Exenterace orbity je indikována u pokročilých nádorů s extrabulbárním šířením nebo při recidivě nádoru v orbitě po předchozí enukleaci.

The aim of intraocular melanoma therapy is to achieve local tumor control, reduce the risk of metastasis development, preserve the eyeball and possibly the visual function of the eye. The choice of therapeutic approach requires a comprehensive view and individual approach to each patient with uveal melanoma. Factors considered include local finding (location, tumor size and shape, tumor activity, central visual acuity, intraocular complications), age and the patient‘s overall physical and psychological condition, as well as the patient‘s wishes. The most widely used method of uveal melanoma treatment is radiotherapy. The effect of radiation is caused by the absorption of ionizing radiation energy, the effect of radiation on the cell is manifested by cell death (depletion), or by a cytogenetic information change (mutation). Brachytherapy uses scleral applicators with radionuclide - ruthenium (Ru-106) applicators dominate in Europe and iodine (I-125) applicators in the USA. In external radiotherapy, the source of ionizing radiation is outside the patient‘s body. Both stereotactic radiosurgery and fractionated stereotactic radiotherapy are used. In the Czech Republic, treatment is carried out using Leksell gamma knife or CyberKnife, while proton therapy dominates in the world. The development of serious radiation complications (radiation retinopathy, neuropathy, neovascular glaucoma, toxic tumor syndrome, etc.) should be considered. Surgical therapy involves a variety of invasive procedures. Iridectomy is performed for iris melanoma. Anteriorly located choroidal melanomas and / or ciliary body melanomas can be resolved by transscleral resection (exoresection). For posterior choroidal melanomas, a combination of external tumor irradiation with pars plana vitrectomy is used. Enucleation is a method of choice in advanced tumors that cannot be effectively irradiated. Orbital exenteration is indicated in advanced tumors with extrabulbar spread or in relapsed tumor after previous enucleation.

• Klíčová slova
• uveální melanom, endoresekce, exoresekce,
• MeSH
• brachyterapie metody   MeSH
• lidé MeSH
• melanom * chirurgie   radioterapie   MeSH
• nádory uvey * chirurgie   radioterapie   MeSH
• radiochirurgie metody   MeSH
• radioizotopy jodu MeSH
• radioterapie metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Terapia zhubných nádorových ochorení patrí medzi najstaršie a zároveň najperspektívnejšie oblasti aplikácie zlúčenín kovov v terapii. Druhá časť prehľadu o metalofarmakách sa zameriava na dejinný vývoj a súčasné využitie komplexných zlúčenín v terapii rakoviny. Najprv sa venuje najznámejšiemu a najúspešnejšiemu liečivu spomedzi metalofarmák – cisplatine. Po stručnom náčrte objavu antineoplastických vlastností tejto zlúčeniny sa zaoberá jej chemickými vlastnosťami, toxicitou, klinickými aplikáciami, mechanizmom účinku a vývojom rezistencie. V ďalšom sú diskutované tiež komplexy iných kovov ako potenciálne chemoterapeutiká, ako aj perspektívne smery výskumu v tejto oblasti. Tento stručný prehľad má za cieľ poskytnúť základnú orientáciu v tejto problematike pre farmaceutov i chemikov, ako aj ostatných záujemcov o danú oblasť z radov odbornej verejnosti.

Therapy of malignant tumors is among the oldest and at the same time the most promising application areas of therapeutic metal complexes. The second part of our survey on metallopharmaceuticals deals with historical development and current state of coordination compounds in cancer therapy. It starts with the most famous and most successful metallodrug – cisplatin. After a brief account of the discovery of the anticancer properties of this substance follows the discussion of its chemical properties, toxicity, clinical application and resistance. Hereafter, complexes of other metals along with innovative research directions are addressed. The aim of this brief survey is to provide basic overview of the area of metallopharmacy, aimed at specialists in pharmacy and chemistry as well as at the general educated public.

• MeSH
• bioanorganická chemie MeSH
• cisplatina terapeutické užití   MeSH
• farmakoterapie metody   MeSH
• komplexní sloučeniny terapeutické užití   MeSH
• kovy * terapeutické užití   MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• platina terapeutické užití   MeSH
• ruthenium terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a search for new chemotherapeutic drugs. Many classes of compounds have been investigated over the years to discover new targets and synergistic mechanisms of action including multicellular targets. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely, [Ru(DIP)2(sq)](PF6) (Ru-sq) (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated with the catecholate moiety. Experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrates that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinized in vitro and in vivo, and the results highlight the promising potential of this complex as a chemotherapeutic agent against cancer.

• MeSH
• chinony chemie   metabolismus   farmakologie   MeSH
• HeLa buňky MeSH
• lidé MeSH
• ligandy MeSH
• myši nahé MeSH
• myši MeSH
• oxidace-redukce účinky léků   MeSH
• protinádorové látky chemie   metabolismus   farmakologie   MeSH
• ruthenium chemie   metabolismus   farmakologie   MeSH
• viabilita buněk účinky léků   fyziologie   MeSH
• xenogenní modely - testy protinádorové aktivity metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH