Novel Organoruthenium(II) Complex C1 Selectively Inhibits Butyrylcholinesterase without Side Effects on Neuromuscular Transmission.

Enzyme butyrylcholinesterase (BChE) shows increased activity in some brain regions after progression of Alzheimer's disease and is therefore one of the therapeutic targets for symptomatic treatment of this neurodegenerative disorder. The organoruthenium(II) complex [(η6-p-cymene)Ru(II)(1-hydroxy-3-methoxypyridine-2(1H)-thionato)pta]PF6 (C1) was designed based on the results of our previous structure-activity studies. Inhibitory activity toward cholinesterase enzymes shows that this complex selectively, competitively, and reversibly inhibits horse serum BChE (hsBChE) with an IC50 value of 2.88 µM. When tested at supra-pharmacological concentrations (30, 60, 90, and 120 µM), C1 had no significant effect on the maximal amplitude of nerve-evoked and directly elicited single-twitch and tetanic contractions. At the highest tested concentration (120 µM), C1 had no effect on resting membrane potential, but significantly decreased the amplitude of miniature end-plate potentials (MEPP) without reducing their frequency. The same concentration of C1 had no effect on the amplitude of end-plate potentials (EPP), however it shortened the half-decay time of MEPPs and EPPs. The decrease in the amplitude of MEPPs and shortening of the half-decay time of MEPPs and EPPs suggest a possible weak inhibitory effect on muscle-type nicotinic acetylcholine receptors (nAChR). These combined results show that, when applied at supra-pharmacological concentrations up to 120 µM, C1 does not importantly affect the physiology of neuromuscular transmission and skeletal muscle contraction.

Exploring pta Alternatives in the Development of Ruthenium-Arene Anticancer Compounds.

Organoruthenium pyrithione (1-hydroxypyridine-2-thione) complexes have been shown in our recent studies to be a promising family of compounds for development of new anticancer drugs. The complex [(η6-p-cymene)Ru(pyrithionato)(pta)]PF6 contains phosphine ligand pta (1,3,5-triaza-7-phosphaadamantane) as a functionality that improves the stability of the complex and its aqueous solubility. Here, we report our efforts to find pta alternatives and discover new structural elements to improve the biological properties of ruthenium anticancer drugs. The pta ligand was replaced by a selection of phosphine, phosphite, and arsine ligands to identify new functionalities, leading to improvement in inhibitory potency towards enzyme glutathione S-transferase. In addition, cytotoxicity in breast, bone, and colon cancers was investigated.

Metal- and metalloid-based compounds to target and reverse cancer multidrug resistance.

Drug resistance remains the major cause of cancer treatment failure especially at the late stage of the disease. However, based on their versatile chemistry, metal and metalloid compounds offer the possibility to design fine-tuned drugs to circumvent and even specifically target drug-resistant cancer cells. Based on the paramount importance of platinum drugs in the clinics, two main areas of drug resistance reversal strategies exist: overcoming resistance to platinum drugs as well as multidrug resistance based on ABC efflux pumps. The current review provides an overview of both aspects of drug design and discusses the open questions in the field. The areas of drug resistance covered in this article involve: 1) Altered expression of proteins involved in metal uptake, efflux or intracellular distribution, 2) Enhanced drug efflux via ABC transporters, 3) Altered metabolism in drug-resistant cancer cells, 4) Altered thiol or redox homeostasis, 5) Altered DNA damage recognition and enhanced DNA damage repair, 6) Impaired induction of apoptosis and 7) Altered interaction with the immune system. This review represents the first collection of metal (including platinum, ruthenium, iridium, gold, and copper) and metalloid drugs (e.g. arsenic and selenium) which demonstrated drug resistance reversal activity. A special focus is on compounds characterized by collateral sensitivity of ABC transporter-overexpressing cancer cells. Through this approach, we wish to draw the attention to open research questions in the field. Future investigations are warranted to obtain more insights into the mechanisms of action of the most potent compounds which target specific modalities of drug resistance.

Zinc pyrithione is a potent inhibitor of PLPro and cathepsin L enzymes with ex vivo inhibition of SARS-CoV-2 entry and replication.

Zinc pyrithione (1a), together with its analogues 1b-h and ruthenium pyrithione complex 2a, were synthesised and evaluated for the stability in biologically relevant media and anti-SARS-CoV-2 activity. Zinc pyrithione revealed potent in vitro inhibition of cathepsin L (IC50=1.88 ± 0.49 µM) and PLPro (IC50=0.50 ± 0.07 µM), enzymes involved in SARS-CoV-2 entry and replication, respectively, as well as antiviral entry and replication properties in an ex vivo system derived from primary human lung tissue. Zinc complexes 1b-h expressed comparable in vitro inhibition. On the contrary, ruthenium complex 2a and the ligand pyrithione a itself expressed poor inhibition in mentioned assays, indicating the importance of the selection of metal core and structure of metal complex for antiviral activity. Safe, effective, and preferably oral at-home therapeutics for COVID-19 are needed and as such zinc pyrithione, which is also commercially available, could be considered as a potential therapeutic agent against SARS-CoV-2.

Kinetic Characterization of Cerium and Gallium Ions as Inhibitors of Cysteine Cathepsins L, K, and S.

Heavy metal ions can disrupt biological functions via multiple molecular mechanisms, including inhibition of enzymes. We investigate the interactions of human papain-like cysteine endopeptidases cathepsins L, K, and S with gallium and cerium ions, which are associated with medical applications. We compare these results with zinc and lead, which are known to inhibit thiol enzymes. We show that Ga3+, Ce3+, and Ce4+ ions inhibit all tested peptidases with inhibition constants in the low micromolar range (between 0.5 µM and 10 µM) which is comparable to Zn2+ ions, whereas inhibition constants of Pb2+ ions are one order of magnitude higher (30 µM to 150 µM). All tested ions are linear specific inhibitors of cathepsin L, but cathepsins K and S are inhibited by Ga3+, Ce3+, and Ce4+ ions via hyperbolic inhibition mechanisms. This indicates a mode of interaction different from that of Zn2+ and Pb2+ ions, which act as linear specific inhibitors of all peptidases. All ions also inhibit the degradation of insoluble elastin, which is a common target of these peptidases in various inflammatory diseases. Our results suggest that these ions and their compounds have the potential to be used as cysteine cathepsin inhibitors in vitro and possibly in vivo.

Structural Characterization, Antimicrobial Activity and BSA/DNA Binding Affinity of New Silver(I) Complexes with Thianthrene and 1,8-Naphthyridine.

Three new silver(I) complexes [Ag(NO3)(tia)(H2O)]n (Ag1), [Ag(CF3SO3)(1,8-naph)]n (Ag2) and [Ag2(1,8-naph)2(H2O)1.2](PF6)2 (Ag3), where tia is thianthrene and 1,8-naph is 1,8-naphthyridine, were synthesized and structurally characterized by different spectroscopic and electrochemical methods and their crystal structures were determined by single-crystal X-ray diffraction analysis. Their antimicrobial potential was evaluated against four bacterial and three Candida species, and the obtained results revealed that these complexes showed significant activity toward the Gram-positive Staphylococcus aureus, Gram-negative Pseudomonas aeruginosa and the investigated Candida species with minimal inhibitory concentration (MIC) values in the range 1.56-7.81 µg/mL. On the other hand, tia and 1,8-naph ligands were not active against the investigated strains, suggesting that their complexation with Ag(I) ion results in the formation of antimicrobial compounds. Moreover, low toxicity of the complexes was detected by in vivo model Caenorhabditis elegans. The interaction of the complexes with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) was studied to evaluate their binding affinity towards these biomolecules for possible insights into the mode of antimicrobial activity. The binding affinity of Ag1-3 to BSA was higher than that for DNA, indicating that proteins could be more favorable binding sites for these complexes in comparison to the nucleic acids.

Structural Isomerism and Enhanced Lipophilicity of Pyrithione Ligands of Organoruthenium(II) Complexes Increase Inhibition on AChE and BuChE.

The increasing number of Alzheimer's disease (AD) cases requires the development of new improved drug candidates, possessing the ability of more efficient treatment as well as less unwanted side effects. Cholinesterase enzymes are highly associated with the development of AD and thus represent important druggable targets. Therefore, we have synthesized eight organoruthenium(II) chlorido complexes 1a-h with pyrithione-type ligands (pyrithione = 1-hydroxypyridine-2(1H)-thione, a), bearing either pyrithione a, its methyl (b-e) or bicyclic aromatic analogues (f-h) and tested them for their inhibition towards electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBuChE). The experimental results have shown that the novel complex 1g with the ligand 1-hydroxyquinoline-2-(1H)-thione (g) improves the inhibition towards eeAChE (IC50 = 4.9 µM) and even more potently towards hsBuChE (IC50 = 0.2 µM) in comparison with the referenced 1a. Moreover, computational studies on Torpedo californica AChE have supported the experimental outcomes for 1g, possessing the lowest energy value among all tested complexes and have also predicted several interactions of 1g with the target protein. Consequently, we have shown that the aromatic ring extension of the ligand a, though only at the appropriate position, is a viable strategy to enhance the activity against cholinesterases.

Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MS.

The development of ruthenium-based complexes for cancer treatment requires a variety of pharmacological studies, one of them being a drug's binding kinetics to serum proteins. In this work, speciation analysis was used to study kinetics of ruthenium-based drug candidates with human serum proteins. Two ruthenium (Ru) complexes, namely [(η6-p-cymene)Ru(1-hydroxypyridine-2(1H)-thionato)Cl] (1) and [(η6-p-cymene)Ru(1-hydroxypyridine-2(1H)-thionato)pta]PF6 (2) (where pta = 1,3,5-triaza-7-phosphaadamantane), were selected. Before a kinetics study, their stability in relevant media was confirmed by nuclear magnetic resonance (NMR). Conjoint liquid chromatography (CLC) monolithic column, assembling convective interaction media (CIM) protein G and diethylamino (DEAE) disks, was used for separation of unbound Ru species from those bound to human serum transferrin (Tf), albumin (HSA) and immunoglobulins G (IgG). Eluted proteins were monitored by UV spectrometry (278 nm), while Ru species were quantified by post-column isotope dilution inductively coupled plasma mass spectrometry (ID-ICP-MS). Binding kinetics of chlorido (1) and pta complex (2) to serum proteins was followed from 5 min up to 48 h after incubation with human serum. Both Ru complexes interacted mainly with HSA. Complex (1) exhibited faster and more extensive interaction with HSA than complex (2). The equilibrium concentration for complex (1) was obtained 6 h after incubation, when about 70% of compound was bound to HSA, 5% was associated with IgG, whereas 25% remained unbound. In contrast, the rate of interaction of complex (2) with HSA was much slower and less extensive and the equilibrium concentration was obtained 24 h after incubation, when about 50% of complex (2) was bound to HSA and 50% remained unbound.

Synthesis, Characterization, Catalytic Activity, and DFT Calculations of Zn(II) Hydrazone Complexes.

Two new Zn(II) complexes with tridentate hydrazone-based ligands (condensation products of 2-acetylthiazole) were synthesized and characterized by infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy and single crystal X-ray diffraction methods. The complexes 1, 2 and recently synthesized [ZnL3(NCS)2] (L3 = (E)-N,N,N-trimethyl-2-oxo-2-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)ethan-1-aminium) complex 3 were tested as potential catalysts for the ketone-amine-alkyne (KA2) coupling reaction. The gas-phase geometry optimization of newly synthesized and characterized Zn(II) complexes has been computed at the density functional theory (DFT)/B3LYP/6-31G level of theory, while the highest occupied molecular orbital and lowest unoccupied molecular orbital (HOMO and LUMO) energies were calculated within the time-dependent density functional theory (TD-DFT) at B3LYP/6-31G and B3LYP/6-311G(d,p) levels of theory. From the energies of frontier molecular orbitals (HOMO-LUMO), the reactivity descriptors, such as chemical potential (µ), hardness (η), softness (S), electronegativity (χ) and electrophilicity index (ω) have been calculated. The energetic behavior of the investigated compounds (1 and 2) has been examined in gas phase and solvent media using the polarizable continuum model. For comparison reasons, the same calculations have been performed for recently synthesized [ZnL3(NCS)2] complex 3. DFT results show that compound 1 has the smaller frontier orbital gap so, it is more polarizable and is associated with a higher chemical reactivity, low kinetic stability and is termed as soft molecule.

Towards Identification of Essential Structural Elements of Organoruthenium(II)-Pyrithionato Complexes for Anticancer Activity.

An organoruthenium(II) complex with pyrithione (2-mercaptopyridine N-oxide) 1 a has previously been identified by our group as a compound with promising anticancer potential without cytotoxicity towards non-cancerous cells. To expand the rather limited research on compounds of this type, an array of novel chlorido and 1,3,5-triaza-7-phosphaadamantane (pta) organoruthenium(II) complexes with methyl-substituted pyrithiones has been prepared. After thorough investigation of the aqueous stability of these complexes, their modes of action have been elucidated at the cellular level. Minor structural alterations in the ruthenium-pyrithionato compounds resulted in fine-tuning of their cytotoxicities. The best performing compounds, 1 b and 2 b, with a chlorido or pta ligand bound to ruthenium, respectively, and a methyl group at the 3-position of the pyrithione scaffold, have been further investigated. Both compounds trigger early apoptosis, induce the generation of reactive oxygen species and G1 arrest in A549 cancer cells, and show no strong interaction with DNA. However, only 1 b also inhibits thioredoxin reductase. Wound healing assays and mitochondrial function evaluation have revealed differences between these two compounds at the cellular level.

Covalent versus Noncovalent Binding of Ruthenium η6 -p-Cymene Complexes to Zinc-Finger Protein NCp7.

Ruthenium-arene complexes are a unique class of organometallic compounds that have been shown to have prominent therapeutic potencies. Here, we have investigated the interactions of Ru-cymene complexes with a zinc-finger protein NCp7, aiming to understand the effects of various ligands on the reaction. Five different binding modes were observed on selected Ru-complexes. Ru-cymene complex can bind to proteins through either noncovalent binding alone or through a combination of covalent and noncovalent binding modes. Moreover, the noncovalent interaction can promote the coordination of RuII to NCp7, resulting synergistic effects of the different ligands. The binding of Ru(Cym) complexes leads to dysfunction of NCp7 through zinc-ejection and structural perturbation. These results indicate that the reactivity of Ru-complexes can be modulated by ligands through different approaches, which could be closely correlated to their different therapeutic effects.

Organoruthenated Nitroxoline Derivatives Impair Tumor Cell Invasion through Inhibition of Cathepsin B Activity.

Lysosomal cysteine peptidase cathepsin B (catB) is an important tumor-promoting factor involved in tumor progression and metastasis representing a relevant target for the development of new antitumor agents. In the present study, we synthesized 11 ruthenium compounds bearing either the clinical agent nitroxoline that was previously identified as potent selective reversible inhibitor of catB activity or its derivatives. We demonstrated that organoruthenation is a viable strategy for obtaining highly effective and specific inhibitors of catB endo- and exopeptidase activity, as shown using enzyme kinetics and microscale thermophoresis. Furthermore, we showed that the novel metallodrugs by catB inhibition significantly impair processes of tumor progression in in vitro cell based functional assays at low noncytotoxic concentrations. Generally, by using metallodrugs we observed an improvement in catB inhibition, a reduction of extracellular matrix degradation and tumor cell invasion in comparison to free ligands, and a correlation with the reactivity of the monodentate halide leaving ligand.

Organometallic ruthenium(II)-arene complexes with triphenylphosphine amino acid bioconjugates: Synthesis, characterization and biological properties.

(p-Cymene)-ruthenium bioconjugates ML (1) and ML2 (2), bearing phosphane ligands substituted with chiral or non-chiral amino acid esters, L, were synthetized and characterized by instrumental methods (NMR, CD, MS) and DFT calculations (using the wB97xD functional). Cytotoxic activity of complexes 1 and 2 was investigated by using human cervical carcinoma cell line (HeLa) and MTT assay. Four (2pG, 2pA, 2mG and 2mA) out of ten synthesized ruthenium complexes showed significant toxicity, with IC50 values of 5-30 µM. Evaluation of the potential biomolecular targets of bioconjugates 2 by UV-Vis, fluorescence and CD spectroscopy revealed no measurable interaction with DNA, but micromolar affinity for proteins. The cytotoxicity of bioconjugates 2 is in correlation with their BSA binding constants, i. e. bioconjugates with lower IC50 values show higher binding affinities towards BSA. Compound 2mG with value of IC50 16 µM was selected for further biological characterization. The higher level of toxicity towards tumor compared to normal cell lines indicates its selective activity, important characteristic for potential medical use. It was detected 2mG caused increase of cells in the S phase of cell cycle and consequential decrease of cells in G0/G1 phase. Additionally, 2mG caused dose- and time-dependent increase of SubG0/G1 cell population, suggesting its ability to induce programmed cell death. Further investigation determined autophagy as the mode of cell death. The role of GSH in HeLa cells response to investigated organometallic ruthenium complexes was confirmed using specific regulators of GSH synthesis, buthionine sulfoximine and N-acetyl-cysteine. Pre-treatment of cells with ethacrynic acid and probenecid emphasized the role of GSH in detoxification of 2mG compound. The amount of total ruthenium accumulation in the cell did not correlate with toxicity of 2pG, 2pA, 2mG and 2mA, suggesting structure dependent differences in either cell uptake or kinetics of ruthenium complexes detoxification. We speculate that ruthenium complexes bind protein-based biomolecules further triggering cell death. Based on the gained knowledge, the synthesis and development of more tumor-specific ruthenium-based complexes as potential anticancer drugs can be expected.

Organoruthenium(II) complexes of acetazolamide potently inhibit human carbonic anhydrase isoforms I, II, IX and XII.

Two acetazolamide (AAZ) complexes with ruthenium(II) η6-p-cymene chloride were synthesised, characterised and tested for their inhibitory effects on several carbonic anhydrase (CA, EC 4.2.1.1) isoforms with pharmacological applications. Against human (h) isoform hCA I, the two complexes showed inhibition constants in the range of 8.5-23.4 nM (AAZ has a KI of 250 nM), against hCA II of 0.48-4.2 nM, whereas against hCA IX of 0.63-3.8 nM and against hCA XII of 0.04-0.52 nM, respectively. These highly effective ruthenium acetazolamide derivatives against the tumour-associated CA isoforms IX and XII warrant further in vivo studies, in hypoxic tumours overexpressing these enzymes.

Synthesis, Biological Evaluation and Docking Studies of Benzoxazoles Derived from Thymoquinone.

Thymoquinone (TQ), a natural compound with antimicrobial and antitumor activity, was used as the starting molecule for the preparation of 3-aminothymoquinone (ATQ) from which ten novel benzoxazole derivatives were prepared and characterized by elemental analysis, IR spectroscopy, mass spectrometry and NMR (¹H, 13C) spectroscopy in solution. The crystal structure of 4-methyl-2-phenyl-7-isopropyl-1,3-benzoxazole-5-ol (1a) has been determined by X-ray diffraction. All compounds were tested for their antibacterial, antifungal and antitumor activities. TQ and ATQ showed better antibacterial activity against tested Gram-positive and Gram-negative bacterial strains than benzoxazoles. ATQ had the most potent antifungal effect against Candida albicans, Saccharomyces cerevisiae and Aspergillus brasiliensis. Three benzoxazole derivatives and ATQ showed the highest antitumor activities. The most potent was 2-(4-fluorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1f). Western blot analyses have shown that this compound inhibited phosphorylation of protein kinase B (Akt) and Insulin-like Growth Factor-1 Receptor (IGF1R ß) in HeLa and HepG2 cells. The least toxic compound against normal fibroblast cells, which maintains similar antitumor activities as TQ, was 2-(4-chlorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1e). Docking studies indicated that 1e and 1f have significant effects against selected receptors playing important roles in tumour survival.

Synthesis and Structural Evaluation of Organo-Ruthenium Complexes with ß-Diketonates.

Four novel ruthenium organometallic complexes: [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-bromophenyl)-1,3-butanedione)Cl] (1), [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-bromophenyl)-1,3-butanedione)pta]PF6 (2), [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-iodophenyl)-1,3-butanedione)Cl] (3) and [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-iodophenyl)-1,3-butanedione)pta]PF6 (4) were synthesized and characterized by elemental analysis, infrared (IR), UV-Vis, NMR and mass spectroscopy and single-crystal X-ray diffraction. The crystal structures and spectroscopic data were compared to the previously published complexes [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-chloro-phenyl)-1,3-butanedione)Cl] (5) and [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-chlorophenyl)-1,3-butanedione)pta]PF6 (6). The pairs of complexes 1 and 3 as well as 2 and 4 are isostructural, with the former crystallizing in triclinic P-1 and the latter in monoclinic P21/c. The ruthenium(II) ion is found in a pseudo-octahedral "piano-stool" geometry in all compounds. Bond lengths and angles are consistent with other complexes of this type. Complexes 2 and 4 exhibit some moderate dynamic disorder. The lack of hydrogen bonding and major π-π interactions means that most of intramolecular interactions are fairly weak and involve halogen atoms present. This was further confirmed by ¹H-NMR spectra, where a significant difference is observed only on the ligand near the halogen atom, following an expected trend. The combined data show that the difference in any activity depends substantially on the type of the ligand's substituted halogen atom.

Interactions of the "piano-stool" [ruthenium(II)(η(6) -arene)(quinolone)Cl](+) complexes with water; DFT computational study.

Full optimizations of stationary points along the reaction coordinate for the hydration of several quinolone Ru(II) half-sandwich complexes were performed in water environment using the B3PW91/6-31+G(d)/PCM/UAKS method. The role of diffuse functions (especially on oxygen) was found crucial for correct geometries along the reaction coordinate. Single-point (SP) calculations were performed at the B3LYP/6-311++G(2df,2pd)/DPCM/saled-UAKS level. In the first part, two possible reaction mechanisms-associative and dissociative were compared. It was found that the dissociative mechanism of the hydration process is kinetically slightly preferred. Another important conclusion concerns the reaction channels. It was found that substitution of chloride ligand (abbreviated in the text as dechlorination reaction) represents energetically and kinetically the most feasible pathway. In the second part the same hydration reaction was explored for reactivity comparison of the Ru(II)-complexes with several derivatives of nalidixic acid: cinoxacin, ofloxacin, and (thio)nalidixic acid. The hydration process is about four orders of magnitude faster in a basic solution compared to neutral/acidic environment with cinoxacin and nalidixic acid as the most reactive complexes in the former and latter environments, respectively. The explored hydration reaction is in all cases endergonic; nevertheless the endergonicity is substantially lower (by ∼6 kcal/mol) in basic environment. © 2016 Wiley Periodicals, Inc.

Investigation of antitumor potential of Ni(II) complexes with tridentate PNO acylhydrazones of 2-(diphenylphosphino)benzaldehyde and monodentate pseudohalides.

Square-planar azido Ni(II) complex with condensation product of 2-(diphenylphosphino)benzaldehyde and Girard's T reagent was synthesized and its crystal structure was determined. Cytotoxic activity of the azido complex and previously synthesized isothiocyanato, cyanato and chlorido Ni(II) complexes with this ligand was examined on six tumor cell lines (HeLa, A549, K562, MDA-MB-453, MDA-MB-361 and LS-174) and two normal cell line (MRC-5 and BEAS-2B). All the investigated nickel(II) complexes were cytotoxic against all tumor cell lines. The newly synthesized azido complex showed selectivity to HeLa and A549 tumor cell lines compared to the normal cells (for A549 IC50 was similar to that of cisplatin). Azido complex interferes with cell cycle phase distribution of A549 and HeLa cells and possesses nuclease activity towards supercoiled DNA. The observed selectivity of the azido complex for some tumor cell lines can be connected with its strong DNA damaging activity.

Special issue: practical applications of metal complexes.

In 1913 Alfred Werner received the Nobel Prize in Chemistry for his work that was of great importance for the development of coordination chemistry. In the years that followed numerous complexes consisting of metal ions and organic ligands were isolated, thus building a strong connection between inorganic and organic chemistry. Coordination compounds have many interesting properties which find diverse applications in numerous aspects of human life. Fourteeen contributions were received for this Special Issue covering very different aspects of metal complexes and their practical applications. The highest number of manuscripts deals with the biological activity of complexes which might potentially be used in the clinical practice. Authors have tested their cytotoxicity, antibacterial activity and enzyme inhibition. Their optical properties were studied in view of their potential use in photodynamic therapy. Moreover, optical properties could also be used for bioanalysis. It is also known that metal complexes are useful catalysts and a few such examples are also described herein. Many other interesting properties and facts about the isolated and described complexes are also reported (radioactivity, design of metal-organic frameworks, etc.).

New synthetic routes for the preparation of ruthenium-1,10-phenanthroline complexes. Tests of cytotoxic and antibacterial activity of selected ruthenium complexes.

Three novel complexes have been prepared through reactions of precursor [(dmso)2H][trans-RuCl4(dmso-S)2] (P) and 1,10-phenanthroline (phen) at different conditions. Whereas the analogs of mer-[RuCl3(dmso-S)(phen)] (1) and [Ru(phen)3]Cl2·6CH3OH (3·6CH3OH) have already been prepared by other synthetic routes before, product (H3O)[RuCl4(phen)]·4H2O (2·4H2O) is unprecedented. In the latter, isolated from highly acidic medium, one strongly bound dmso molecule in precursor P was substituted by chloride. Biological activity of 1 and previously isolated ruthenium-purine complexes ([mer-RuCl3(dmso-S)(acv)(CH3OH)] (4) (acv = acyclovir); [trans-RuCl4(dmso-S)(guaH)] (5) (guaH = protonated guanine)) was tested and compared. These data show that compounds 1, 4 and 5 are slightly cytotoxic against B-16 malignant melanoma cells but not against non-transformed V-79-379A cells. It seems that coordinated phen ligand increases the cytotoxicity of 1 in comparison to ruthenium precursor. The inability of tested compounds to induce lysis of bovine erythrocytes suggests that their cytotoxic effect is not due to the membrane damage.