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
• Apoptosis drug effects   MeSH
• Cell Membrane drug effects   metabolism   MeSH
• Quinoxalines * chemistry   pharmacology   chemical synthesis   MeSH
• Photochemotherapy * MeSH
• Photosensitizing Agents * pharmacology   chemistry   chemical synthesis   therapeutic use   MeSH
• Coordination Complexes * pharmacology   chemistry   chemical synthesis   therapeutic use   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Neoplastic Stem Cells * drug effects   pathology   MeSH
• Colonic Neoplasms * drug therapy   pathology   MeSH
• Antineoplastic Agents * pharmacology   chemistry   chemical synthesis   therapeutic use   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Ruthenium * chemistry   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article 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
• Cell Adhesion drug effects   MeSH
• Coordination Complexes * pharmacology   chemistry   therapeutic use   MeSH
• Humans MeSH
• Neoplasm Metastasis prevention & control   drug therapy   MeSH
• Cell Line, Tumor MeSH
• Cell Movement * drug effects   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents * pharmacology   chemistry   therapeutic use   MeSH
• Ruthenium * chemistry   pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article 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
• Coordination Complexes * chemistry   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Drug Carriers MeSH
• Computer Simulation MeSH
• Antineoplastic Agents * chemistry   MeSH
• Ruthenium * chemistry   MeSH
• Drug Screening Assays, Antitumor MeSH
• Triple Negative Breast Neoplasms * drug therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article 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
• Homeostasis MeSH
• Coordination Complexes * pharmacology   MeSH
• Humans MeSH
• Mitochondria MeSH
• Cell Line, Tumor MeSH
• Neoplasms * drug therapy   MeSH
• Antineoplastic Agents * pharmacology   therapeutic use   MeSH
• Ruthenium * pharmacology   MeSH
• Calcium MeSH
• Water MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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
• Phosphines MeSH
• Coordination Complexes * chemistry   pharmacology   MeSH
• Humans MeSH
• Ligands MeSH
• Cell Line, Tumor MeSH
• Ovarian Neoplasms * MeSH
• Antineoplastic Agents * chemistry   MeSH
• Ruthenium * chemistry   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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 chemistry   pharmacology   MeSH
• Coordination Complexes chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Ligands MeSH
• Molecular Structure MeSH
• Tumor Cells, Cultured MeSH
• DNA Damage MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Pyridines chemistry   pharmacology   MeSH
• Ruthenium chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Cell Survival drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article 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
• Chemistry, Bioinorganic MeSH
• Cisplatin therapeutic use   MeSH
• Drug Therapy methods   MeSH
• Coordination Complexes therapeutic use   MeSH
• Metals * therapeutic use   MeSH
• Humans MeSH
• Neoplasms * drug therapy   MeSH
• Platinum therapeutic use   MeSH
• Ruthenium therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review 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
• Quinones chemistry   metabolism   pharmacology   MeSH
• HeLa Cells MeSH
• Humans MeSH
• Ligands MeSH
• Mice, Nude MeSH
• Mice MeSH
• Oxidation-Reduction drug effects   MeSH
• Antineoplastic Agents chemistry   metabolism   pharmacology   MeSH
• Ruthenium chemistry   metabolism   pharmacology   MeSH
• Cell Survival drug effects   physiology   MeSH
• Xenograft Model Antitumor Assays methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The current epidemic of antibiotic-resistant infections urges to develop alternatives to less-effective antibiotics. To assess anti-bacterial potential, a novel coordinate compound (RU-S4) was synthesized using ruthenium-Schiff base-benzimidazole ligand, where ruthenium chloride was used as the central atom. RU-S4 was characterized by scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy (EDS), and Raman spectroscopy. Antibacterial effect of RU-S4 was studied against Staphylococcus aureus (NCTC 8511), vancomycin-resistant Staphylococcus aureus (VRSA) (CCM 1767), methicillin-resistant Staphylococcus aureus (MRSA) (ST239: SCCmecIIIA), and hospital isolate Staphylococcus epidermidis. The antibacterial activity of RU-S4 was checked by growth curve analysis and the outcome was supported by optical microscopy imaging and fluorescence LIVE/DEAD cell imaging. In vivo (balb/c mice) infection model prepared with VRSA (CCM 1767) and treated with RU-S4. In our experimental conditions, all infected mice were cured. The interaction of coordination compound with bacterial cells were further confirmed by cryo-scanning electron microscope (Cryo-SEM). RU-S4 was completely non-toxic against mammalian cells and in mice and subsequently treated with synthesized RU-S4.

• MeSH
• Anti-Bacterial Agents chemistry   pharmacology   MeSH
• Bacteria drug effects   MeSH
• Cell Line MeSH
• Coordination Complexes chemistry   pharmacology   MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Molecular Structure MeSH
• Mice MeSH
• Spectrum Analysis, Raman MeSH
• Ruthenium chemistry   MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Východiska: Organokovové sloučeniny jsou látky, které obsahují vazbu uhlík- kov. Z biologického hlediska jsou tyto sloučeniny všeobecně považovány za látky toxické pro živé organizmy. Díky tomu však současně vykazují terapeutický potenciál, především jako protinádorová nebo antimikrobiální léčiva. Jsou variabilní co do struktury, obvykle bez náboje a většinou mají lipofilní charakter. V oblasti medicíny se doposud nejvíce osvědčily deriváty platiny, především cisplatina, která je jednou z nejdéle používaných chemoterapeutických látek. Na její úspěchy se vědecká komunita snaží navázat syntézou dalších organokovových sloučenin vykazujících výraznější protinádorové účinky a současně nižší cytotoxicitu vůči zdravým tkáním. Velká pozornost je upínána zejména ke sloučeninám nesoucím atomy železa, titanu nebo ruthenia. Cíl: V této práci jsme se zaměřili na popis nejdůležitějších sloučenin obsahujících ve své struktuře atomy železa, titanu nebo ruthenia, které by potenciálně mohly být využity při léčbě onkologických onemocnění, a zahrnuli jsme také mechanizmus účinku u některých podrobněji zkoumaných sloučenin. Uvedené sloučeniny byly úspěšně testovány v preklinických studiích vč. zvířecích modelů a některé byly testovány i v rámci klinických studií. Navzdory skutečnosti, že řada doposud testovaných organometalických látek v klinických hodnoceních neuspěla, stále je k dispozici několik kandidátů, u kterých se očekává postoupení do dalších fází klinických studií ať už samostatně, nebo jako součást kombinované chemoterapeutické léčby. Jedná se zejména o sloučeniny obsahující ruthenium, které mají vysoký potenciál použití díky své nízké cytotoxicitě, ale současně vysoké schopnosti inhibovat neoangiogenezi a tvorbu metastáz.

Background: Organometallic compounds are chemical substances containing a carbon-metal bond. From a biological point of view, these compounds are generally considered to be toxic for living organisms. They may exert therapeutic potential, especially as anticancer or antimicrobial drugs. Their structural variability and usually uncharged and mostly lipophilic character are particularly advantageous properties. Platinum derivatives (predominately cisplatin) are the most proven advantageous agents in the medical field. The success of cisplatin has led the scientific community to focus on the synthesis of other organometallic compounds with improved anti-tumour effects and lower cytotoxicity towards healthy tissues. Close attention is focused on compounds bearing atoms of iron, titanium or ruthenium. Purpose: Here, we focus on summarising a description of the most important compounds containing iron, titanium or ruthenium atoms in their structure, showing potential application in cancer treatment including the mechanism of action for some of the most commonly studied compounds. The reported structures were used successfully in preclinical studies including animal models and progressed to various stages of human clinical trials. Despite the failure of some of these compounds, there are still several candidates which are expected to progress to the late stages of the clinical trials either alone or as part of combined chemotherapy. Ruthenium-containing substances in particular show high potential for utilisation in cancer treatment due to low cytotoxicity associated with the ability to block neoangiogenesis and metastasis development.

• MeSH
• Clinical Studies as Topic MeSH
• Humans MeSH
• Neoplasms * drug therapy   MeSH
• Organometallic Compounds * therapeutic use   MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Ruthenium therapeutic use   MeSH
• Titanium therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH