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The antibacterial activity of 22 thiolato-bridged dinuclear ruthenium(II)-arene compounds was assessedin vitroagainstEscherichia coli, Streptococcus pneumoniaeandStaphylococcus aureus. None of the compounds efficiently inhibited the growth of the threeE. colistrains tested and only compound5exhibited a medium activity against this bacterium (MIC (minimum inhibitory concentration) of 25 μM). However, a significant antibacterial activity was observed againstS. pneumoniae, with MIC values ranging from 1.3 to 2.6 μM for compounds1-3,5and6. Similarly, compounds2,5-7and20-22had MIC values ranging from 2.5 to 5 μM againstS. aureus.The tested diruthenium compounds have a bactericidal effect significantly faster than that of penicillin. Fluorescence microscopy assays performed onS. aureususing the BODIPY-tagged diruthenium complex15showed that this type of metal compound enter the bacteria and do not accumulate in the cell wall of gram-positive bacteria. Cellular internalization was further confirmed by inductively coupled plasma mass spectrometry (ICP-MS) experiments. The nature of the substituents anchored on the bridging thiols and the compounds molecular weight appear to significantly influence the antibacterial activity. Thus, if overall a decrease of the bactericidal effect with the increase of compounds’ molecular weight is observed, however the complexes bearing larger benzo-fused lactam substituents had low MIC values. This first antibacterial activity screening demonstrated that the thiolato-diruthenium compounds exhibit promising activity againstS. aureusandS. pneumoniaeand deserve to be considered for further studies.

The synthesis, photophysical properties and antiparasitic efficacy against Toxoplasma gondii β-gal (RH strain tachyzoites expressing β-galactosidase) grown in human foreskin fibroblast monolayers (HFF) of a series of 15 new conjugates BODIPY-trithiolato-bridged dinuclear ruthenium(II)-arene complexes are reported (BODIPY = 4,4-difluoro-4-bora-3a,4a-diaza- s -indacene, derivatives used as fluorescent markers). The influence of the bond type (amide vs ester), as well as that of the length and nature (alkyl vs aryl) of the spacer between the dye and the diruthenium(II) complex moiety, upon the fluorescence and the biological activity were evaluated. The assessed photophysical properties revealed that despite an important fluorescence quenching effect observed after conjugating the BODIPY to the diruthenium unit, the hybrids could nevertheless be used as fluorescent tracers. Although the antiparasitic activity of these series of conjugates appears limited, the compounds demonstrate potential as fluorescent probes to be used for investigating the intracellular trafficking of trithiolato-bridged dinuclear Ru(II)-arene complexes in vitro .

The synthesis, characterization, photophysical and biological properties of 13 new conjugate coumarin‐diruthenium(II)⋅arene complexes against Toxoplasma gondii are presented. For all conjugate organometallic unit/coumarins, an almost complete loss of fluorescence efficacy was observed. However, the nature of the fluorophore, the type of bonding, the presence and length of a linker between the coumarin dye and the ruthenium(II) moiety, and the number of dye units influenced their biological properties. The in vitro activity against a transgenic T. gondii strain grown in human foreskin fibroblasts (HFF) leads to IC50 values for T. gondii β‐gal from 105 to 735 nM. Of note is that nine compounds displayed lower IC50 than the standard drug pyrimethamine. One compound applied at its IC50 did not affect B‐cell proliferation but had an impact on T‐cell proliferation in murine splenocyte cultures. Transmission electron microscopy of T. gondii β‐gal‐infected HFF showed that treatment predominantly affected the parasites’ mitochondrion., The (para)site for treatment: Thirteen coumarin‐diruthenium(II)⋅arene conjugates were evaluated against a transgenic T. gondii strain grown in human foreskin fibroblasts (HFF). The IC50 values ranged from 105 to 735 nM, with nine compounds displaying a lower IC50 than the standard drug pyrimethamine. TEM of T. gondii‐infected HFF showed that treatment predominantly affected the parasites’ mitochondrion.

A structure activity relationship (SAR) study of a library of 56 compounds (54 ruthenium and 2 osmium derivatives) based on the trithiolato-bridged dinuclear ruthenium(II)-arene scaffold (general formula [(η6-arene)2Ru2(μ2-SR)3]+, symmetric and [(η6-arene)2Ru2(μ2-SR1)2(μ2-SR2)]+, mixed, respectively) is reported. The 56 compounds (of which 34 are newly designed drug candidates) were synthesized by introducing chemical modifications at the level of bridge thiols, and they were grouped into eight families according to their structural features. The selected fittings were guided by previous results and focused on a fine-tuning of the physico-chemical and steric properties. Newly synthesized complexes were characterized by NMR spectroscopy, mass spectrometry and elemental analysis, and four single-crystal X-ray structures were obtained. The in vitro biological assessment of the compounds was realized by applying a three-step screening cascade: (i) evaluation of the activity against Toxoplasma gondii RH strain tachyzoites expressing β-galactosidase (T. gondii-β-gal) grown in human foreskin fibroblast monolayers (HFF) and assessment of toxicity in non-infected HFF host cells; (ii) dose-response assays using selected compound, and (iii) studies on the effects in murine splenocytes. A primary screening was performed at 1 and 0.1 μM, and resulted in the selection of 39 compounds that inhibited parasite proliferation at 1 μM by more than 95% and reduced the viability of HFF by less than 49%. In the secondary screening, dose-response assays showed that the selected compounds exhibited half maximal inhibitory concentration (IC50) values for T. gondii-β-gal between 0.01 μM and 0.45 μM, with 30 compounds displaying an IC50 lower than 0.1 μM. When applied to non-infected HFF monolayers at 2.5 μM, 8 compounds caused more than 90% and 31 compounds more than 30% viability impairment. The tertiary screening included 14 compounds that did not cause HFF viability loss higher than 50% at 2.5 μM. These derivatives were assessed for potential immunosuppressive activities. First, splenocyte viability was assessed after treatment of cells with concanavalin A (ConA) and lipopolysaccharide (LPS) with compounds applied at 0.1 and 0.5 μM. Subsequently, the 5 compounds exhibiting the lowest splenocyte toxicity were further evaluated for their potential to inhibit B and T cell proliferation. Overall, compound 55 [(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-o-CF3)2(μ2-SC6H4-p-OH)]Cl exhibited the most favorable features, and will be investigated as a scaffold for further optimization in terms of anti-parasitic efficacy and drug-like properties

The synthesis, characterization, and in vitro antiparasitic and anticancer activity evaluation of new conjugates containing two and three dinuclear trithiolato-bridged ruthenium(II)-arene units are presented. Antiparasitic activity was evaluated using transgenic Toxoplasmagondii tachyzoites constitutively expressing &beta, galactosidase grown in human foreskin fibroblasts (HFF). The compounds inhibited T.gondii proliferation with IC50 values ranging from 90 to 539 nM, and seven derivatives displayed IC50 values lower than the reference compound pyrimethamine, which is currently used for treatment of toxoplasmosis. Overall, compound flexibility and size impacted on the anti-Toxoplasma activity. The anticancer activity of 14 compounds was assessed against cancer cell lines A2780, A2780cisR (human ovarian cisplatin sensitive and resistant), A24, (D-)A24cisPt8.0 (human lung adenocarcinoma cells wild type and cisPt resistant subline). The compounds displayed IC50 values ranging from 23 to 650 nM. In A2780cisR, A24 and (D-)A24cisPt8.0 cells, all compounds were considerably more cytotoxic than cisplatin, with IC50 values lower by two orders of magnitude. Irrespective of the nature of the connectors (alkyl/aryl) or the numbers of the di-ruthenium units (two/three), ester conjugates 6&ndash, 10 and 20 exhibited similar antiproliferative profiles, and were more cytotoxic than amide analogues 11&ndash, 14, 23, and 24. Polynuclear conjugates with multiple trithiolato-bridged di-ruthenium(II)-arene moieties deserve further investigation.

Tethering known drugs to a metalorganic moiety is an efficient approach for modulating the anticancer, antibacterial, and antiparasitic activity of organometallic complexes. This study focused on the synthesis and evaluation of new dinuclear ruthenium(II)–arene compounds linked to several antimicrobial compounds such as dapsone, sulfamethoxazole, sulfadiazine, sulfadoxine, triclosan, metronidazole, ciprofloxacin, as well as menadione (a 1,4-naphtoquinone derivative). In a primary screen, 30 compounds (17 hybrid molecules, diruthenium intermediates, and antimicrobials) were assessed for in vitro activity against transgenic T.&nbsp, gondii tachyzoites constitutively expressing β-galactosidase (T.&nbsp, gondii β-gal) at 0.1 and 1 µM. In parallel, the cytotoxicity in noninfected host cells (human foreskin fibroblasts, HFF) was determined by an alamarBlue assay. When assessed at 1 µM, five compounds strongly impaired parasite proliferation by &gt, 90%, and HFF viability was retained at 50% or more, and they were further subjected to T.&nbsp, gondii β-gal dose-response studies. Two compounds, notably 11 and 13, amide and ester conjugates with sulfadoxine and metronidazole, exhibited low IC50 (half-maximal inhibitory concentration) values 0.063 and 0.152 µM, and low or intermediate impairment of HFF viability at 2.5 µM (83 and 64%). The nature of the anchored drug as well as that of the linking unit impacted the biological activity.

Chlorambucil (CLB) derivatives with long fluorous (referred to as 1 and 2) or hydrocarbon (3) chains have been evaluated in a series of in vitro and in vivo assays. In cell viability inhibition assays, both derivatives 2 and 3 show selective cytotoxicity towards human immortalized endothelial cells (ECRF24), while lacking activity against human ovarian carcinoma cell lines, contrary to the activity of CLB. Compound 3 also significantly inhibits sprout formation in an in vivo model of induced angiogenesis following photodynamic vascular occlusion in the chorioallantoic membrane (CAM) model. Moreover, intravenous administration of CLB and its derivatives in the non-perturbed CAM vasculature resulted in important changes in the vascular morphology. Notably, the growth of human ovarian carcinoma tumors implanted on the CAM was significantly inhibited by 2 and 3, i.e. by 70 and 53%, respectively, compared to vehicle treated tumors. Taken together, these results show that anchoring long fluorous or hydrocarbon chains to the carboxylic group of CLB leads to compounds showing increased anti-angiogenic activity which also effectively inhibit tumor growth in vivo.

Two bifunctional ruthenium(II)-p-cymene complexes with perfluorinated side chains, attached via pyridine ligands, have been evaluated in a series of in vitro and in vivo assays. Their effects on human endothelial (ECRF24 and HUVEC) cells, noncancerous human embryonic kidney (HEK-293) cells, and various human tumor cells were investigated. The complex with the shorter chain, 1, inhibits the proliferation of the tumor cell lines and ECRF24, whereas 2 selectively inhibits ECRF24 and HUVEC proliferation. Neither inhibits the migration of ECRF24 cells whereas both compounds inhibit sprout formation in HUVEC cells. Using three preclinical models, i.e., vasculature formation in the chorioallantoic membrane (CAM) of the chicken embryo, human A2780 ovarian carcinoma tumors xenografted on the CAM, and human LS174T colorectal adenocarcinoma tumors grown in athymic mice, the angiostatic and anticancer activities of these two complexes were studied. Overall, 1 inhibited tumor growth predominantly through an anticancer effect whereas 2 inhibited tumor growth predominately via an antiangiogenic mechanism.

Hyperthermia used as an adjuvant with chemotherapy is highly promising in the treatment of certain cancers., Hyperthermia used as an adjuvant with chemotherapy is highly promising in the treatment of certain cancers. Currently, the small molecule drugs used in combination with hyperthermia were not designed for this application. Herein, we report the evaluation of a chlorambucil and a ruthenium compound modified with a long fluorous chain, which exhibit thermoresponsive activity in colorectal adenocarcinoma xenografts in athymic mice in combination with mild hyperthermia (42 °C). Intraperitoneal injection of the derivatives followed by local hyperthermia showed a synergistic tumor growth reduction by 79% and 90% for the chlorambucil and ruthenium-based derivatives, respectively, with the latter exhibiting a higher synergy in combination with hyperthermia compared to the monotherapies. Histological analysis shows that both derivatives in combination with hyperthermia significantly decrease the number of proliferating tumor cells.

Osmium compounds are attracting increasing attention as potential anticancer drugs. In this context, a series of bifunctional organometallic osmium(II)-p-cymene complexes functionalized with alkyl or perfluoroalkyl groups were prepared and screened for their antiproliferative activity. Three compounds from the series display selectivity toward cancer cells, with moderate cytotoxicity observed against human ovarian carcinoma (A2780) cells, whereas no cytotoxicity was observed on non-cancerous human embryonic kidney (HEK-293) cells and human endothelial (ECRF24) cells. Two of these three cancer-cell-selective compounds induce cell death largely via apoptosis and were also found to disrupt vascularization in the chicken embryo chorioallantoic membrane (CAM) model. Based on these promising properties, these compounds have potential clinical applications.

Hyperthermia is currently being explored as an adjuvant treatment to conventional therapies with chemotherapeutic agents based on thermoresponsive macromolecules. Although the concept of hyperthermia has existed for many years it has yet to become routinely used in the clinical management of cancer. The development of small thermoresponsive molecules could help to change this paradigm. Temperature-sensitive compounds have recently been developed by covalently modifying drug and drug-like molecules with thermomorphic perfluorinated appendages. Lead thermoresponsive compounds have been validated in a pre-clinical model, displaying high tumor growth inhibition, with strong synergies observed between hyperthermia and the thermomorphic compounds.

Ionic liquids incorporating a polymerizable anion were prepared in a facile manner and used to fabricate stable titania nanoparticle films. The nanotitania was directly patterned by UV imprinting using micrometer size test structures in a polydimethylsiloxane mold. The resulting resist microstructures are resistant to cracking with only slight shrinkage observed for the system made using a hydrophobic ionic liquid. Because ionic liquids with a plethora of different physical and chemical properties can be made (designed) in a facile manner their application in this facile process instead of organic solvents could lead to many new types of functional materials.

The phosphorylation of a series of diaminopyridines (2,3-, 3,4-, 2,5- and 2,6-diaminopyridine), with various molecular equivalents of chlorodiphenylphosphine in the presence of TEA has been studied. Notably, phosphorylation of 2,3- and 3,4-diaminopyridine affords compounds with diphosphinoamine (P-N-P) and iminobiphosphine (N=P-P) entities co-existing in the same molecule. Phosphorylations of 2,5- and 2,6-diaminopyridine afford compounds containing only diphosphinoamine units. The solid-state structure of three compounds has been determined including the first example of a crystallographically characterized compound containing both a diphosphinoamine group and an iminobiphosphine group in the same structure.

A ruthenium(II) arene complex with a perfluoroalkyl ligand was found to display remarkable selectivity toward cancer cells. IC50 values on several cancer cell lines are in the range of 25 45 µM and no cytotoxic effect was observed on nontumorigenic (HEK 293) cells at concentrations up to 500 µM (the maximum concentration tested). Consequently this complex was used as the basis for the development of a number of related derivatives which were screened in cancerous and noncancerous cell lines. The lead compound was then evaluated in vivo for antiangiogenic activity in the CAM model and in a xenografted ovarian carcinoma tumor (A2780) grown on the CAM. A 90 reduction in the tumor growth was observed. © 2014 American Chemical Society.

Application of mild hyperthermia can increase the cytotoxicity of anticancer drugs in tumour cells. In this report we describe low molecular weight thermoactive ruthenium based drugs with fluorous chains that are selectively triggered by mild hyperthermia. The organometallic complexes were prepared characterized and evaluated for their in vitro cytotoxicity against a panel of human cancer cell lines and non cancerous immortalized cells. The compounds show considerable chemo thermal selectivity towards cancer cells (ca. 5 µM versus >500 µM for healthy cells) for the compound with the longest fluorous chain. This journal is © The Royal Society of Chemistry 2014.

A series of cross linked ionic polymers based on styrene functionalized imidazolium salts with chloride hexafluorophosphate or tetrafluoroborate counter anions have been prepared and characterized using a range of analytical and spectroscopic techniques and electron microscopy. The polymer with the chloride anion is an efficient catalyst for the cycloaddition of carbon dioxide with epoxides to afford cyclic carbonates. The cross linked polymer is insoluble in organic solvents and is highly stable and therefore can be easily recycled and reused. © 2013 The Royal Society of Chemistry.

Compounds that combine metal-based drugs with covalently linked targeted organic agents have been shown, in some instances, to exhibit superior anticancer properties compared to the individual counterparts. Within this framework, we prepared a series of organometallic ruthenium(II)- and osmium(II)-p-cymene complexes modified with the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin and diclofenac. The NSAIDs are attached to the organometallic moieties via monodentate (pyridine/phosphine) or bidentate (bipyridine) ligands, affording piano-stool Ru(II) and Os(II) arene complexes of general formula [M(η(6)-p-cymene)Cl2(N)], where N is a pyridine-based ligand, {2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-3-(pyridin-3-yl)propanoate} or {2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl-3-(pyridin-3-yl)propanoate}, [M(η(6)-p-cymene)Cl2(P)], where P is a phosphine ligand, {2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-4-(diphenylphosphanyl)benzoate} or {2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl-4-(diphenylphosphanyl)benzoate, and [M(η(6)-p-cymene)Cl(N,N')][Cl], where N,N' is a bipyridine-based ligand, (4'-methyl-[2,2'-bipyridin]-4-yl)methyl-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate), (4'-methyl-[2,2'-bipyridin]-4-yl)methyl-2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate), (bis(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl)[2,2'-bipyridine]-5,5'-dicarboxylate), or (bis(2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl)[2,2'-bipyridine]-5,5'-dicarboxylate). The antiproliferative properties of the complexes were assessed in human ovarian cancer cells (A2780 and A2780cisR, the latter being resistant to cisplatin) and nontumorigenic human embryonic kidney (HEK-293) cells. Some of the complexes are considerably more cytotoxic than the original drugs and also display significant cancer cell selectivity.

Four arene osmium complexes were prepared containing derivatives of ethacrynic acid, a potent inhibitor of glutathione S-transferases, either by direct coordination or via N- or P-donor ligands. The complexes were characterized by spectroscopic and analytical methods and, for Os(η6-p-cymene)(acetylacetonato)(2-(2,3-dichloro-4-(2-ethylenebutanoyl)phenoxy)acetato) and Os(η6-p-cymene)Cl2(2-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetoxy)ethyl nicotinato), by single-crystal X-ray diffraction. The cytotoxicity of the complexes toward human ovarian cancer cells and nontumorous human embryonic kidney cells was investigated, and two of the complexes, for which ruthenium analogues are known, helped to delineate the influence of the metal ion. Inhibition studies of intracellular glutathione S-transferases (GSTs, detoxification enzymes implicated in drug resistance) indicate that the observed cytotoxicity of the complexes involves GST inhibition, as well as other targets following dissociation of the ethacrynic acid group from the osmium(II) ion., We thank the Swiss National Science Foundation, MINECO of Spain (Projects CTQ2014-52799-P and CTQ2014-51912-REDC), the Diputacion General de Aragón (E-35), the European Social Fund (FSE and FEDER), and the University of Pisa (PRA 2015) for financial support. M.P.G. (FPI grant) thanks MINECO for funding.

In order to determine the real significance of the 4'-phenolic group in the antimalarial activity and/or cytotoxicity of amodiaquine (AQ), analogues for which this functionality was shifted or modified were synthesized. Good in vitro antimalarial activity was obtained for compounds unable to form intramolecular hydrogen bond. Among the compounds synthesized, new amino derivative 5 displayed the greatest selectivity index towards the most CQ-resistant strain tested and was active in mice infected by Plasmodium berghei.

A versatile methodology for the synthesis of some new 4-aminoquinoquinoline antimalarial drugs, using Csp2–Csp2 and Csp2–Csp3 Suzuki–Miyaura cross-coupling reactions as a key step, is presented. The proposed strategy allowed the synthesis of 26 new amodiaquine (AQ) and amopyroquine (ApQ) derivatives. These new compounds constitute the base of the development of a new library, designed in order to obtain derivatives that present not only improved antimalarial activity, but also a better stability towards bioactivation in potentially toxic metabolites.

Following the identification of [Ru(eta(6)-p-cymene)Cl-2(1H,1H,2H,2H-perfluorodecyl-3-(pyridin-3-yl)propanoate)], a ruthenium(II)arene complex with a perfluoroalkyl-modified ligand that displays remarkable in vitro cancer cell selectivity, a series of structurally related compounds were designed. In the new derivatives, the p-cymene ring and/or the chloride ligands are substituted by other ligands to modulate the steric bulk or aquation kinetics. The new compounds were evaluated in both in vitro (cytotoxicity and migration assays) and in vivo (chicken chorioallantoic membrane) models and were found to exhibit potent antivascular effects.

Dasatinib is an orally active nonselective tyrosine kinase inhibitor used to treat certain types of adult leukemia. By inhibiting PDGFR-beta and SFKs in both tumor cells and tumor associated endothelial cells, dasatinib inhibits tumor growth and angiogenesis. Herein, dasatinib derivatives modified with hydrophobic chains were prepared and evaluated for their in vitro antiproliferative selectivity and their in vivo antiangiogenic activity. For one of the derivatives, modified with a long perfluorinated chain, a significant enhancement in antiangiogenic activity was observed. Combined, these results suggest a possible generic route to modulate the angiostatic activity of drugs.

International audience; Amodiaquine remains one of the most prescribed antimalarial 4-aminoquinoline. To assess the importance of the 4'-hydroxyl group and subsequent hydrogen bond in the antimalarial activity of amodiaquine (AQ), a series of new analogues in which this functionality was replaced by various amino groups was synthesized. The incorporation of a 3'-pyrrolidinamino group instead of the 3'-diethylamino function of AQ allowed the development of a parallel series of amopyroquine derivatives. The compounds were screened against both chloroquine (CQ)-sensitive and -resistant strains of Plasmodium falciparum and their cytotoxicity evaluated upon the MRC5 cell line. Antimalarial activity in a low nanomolar range was recorded showing that the 4'-hydroxy function can be successfully replaced by various amino substituents in terms of activity without any influence of the level of CQ-resistance of the strains. Furthermore the ability of the compounds to inhibit beta-hematin formation was measured in order to discuss the mechanism of action of these new compounds. Compounds 7d and 8d exhibit a high selectivity index and may be considered as promising leads for further development.

In order to determine the real significance of the 4'-phenolic group in the antimalarial activity and/or cytotoxicity of amodiaquine (AQ), analogues for which this functionality was shifted or modified were synthesized. Good in vitro antimalarial activity was obtained for compounds unable to form intramolecular hydrogen bond. Among the compounds synthesized, new amino derivative 5 displayed the greatest selectivity index towards the most CQ-resistant strain tested and was active in mice infected by Plasmodium berghei.

A versatile methodology for the synthesis of some new 4-aminoquinoquinoline antimalarial drugs, using Csp2–Csp2 and Csp2–Csp3 Suzuki–Miyaura cross-coupling reactions as a key step, is presented. The proposed strategy allowed the synthesis of 26 new amodiaquine (AQ) and amopyroquine (ApQ) derivatives. These new compounds constitute the base of the development of a new library, designed in order to obtain derivatives that present not only improved antimalarial activity, but also a better stability towards bioactivation in potentially toxic metabolites.

An ionic liquid encompassing a bulky tertiary amine was synthesized and used as a dual solvent-reactant for the formation of a frustrated Lewis pair with tris(pentafluorophenyl) borane, forming a pseudo-frustrated Lewis pair-ionic liquid system. The ionic liquid-LA system is prone to self-ionization, i.e. with the formation of iminium and boron hydride species, which are able to form adducts with CO2. Compared to frustrated Lewis pairs operating in organic solvents of low polarity, more forcing conditions are required for the ionic liquid system. Calculations indicate that the anion of the ionic liquid interacts with the Lewis acidic boron center, hindering reactivity, and rationalizing the low reactivity observed. (C) 2017 Elsevier B.V. All rights reserved.

A new family of organometallic p-cymene ruthenium(II) and osmium(II) complexes conjugated to ethacrynic acid, a glutathione transferase (GST) inhibitor, is reported. The ethacrynic acid moiety (either one or two) is tethered to the arene ruthenium(II) and osmium(II) fragments via strongly coordinating modified bipyridine ligands. The solid-state structure of one of the complexes, i.e. [Os(eta(6)-p-cymene)CI][(4'-methyl-[2,2'-bipyridin]-4-y1)methyl-2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetate]Cl, was established by single-crystal X-ray diffraction, corroborating the expected structure. The complexes are efficient inhibitors of GST P1-1, an enzyme expressed in cancer cells and implicated in drug resistance, and are cytotoxic to the GST-overexpressing chemoresistant A2780cisR ovarian cancer cell line.

In this study, we explore the supramolecular association and phase separation properties of non-covalent analogues of polystyrene-b-polyethylene glycol (PS-b-PEG) and polystyrene-b-polyisoprene (PS-b-PI) diblock copolymers. For this purpose, a PS homopolymer is end-functionalized with a quadruple hydrogen bonding unit and PEG and PI homopolymers are end-functionalized with a hetero-complementary hydrogen bonding group. Hetero-dimerization between the complementary chain ends of the respective homopolymers furnishes supramolecular (s) PS-s-PEG and PS-s-PI diblock copolymers with phase-separation studies in thin films and bulk demonstrating that the non-covalent block copolymers are capable of self-organizing into nanostructured morphologies reminiscent of their covalent analogues.

Pyridine- and phosphine-based ligands modified with ethacrynic acid (a broad acting glutathione transferase inhibitor) were prepared and coordinated to ruthenium(II)-arene complexes and to a ruthenium(III) NAMI-A type complex. All the compounds (ligands and complexes) were fully characterized by analytical and spectroscopic methods and, in one case, by single-crystal X-ray diffraction. The in vitro anticancer activity of the compounds was studied, with the compounds displaying moderate cytotoxicity toward the human ovarian cancer cell lines. All the complexes led to similar levels of residual GST activity in the different cell lines, irrespective of the stability of the Ru-ligand bond.

Hydrogen bonding in ionic liquids based on the 1-(2'-hydroxylethyl)-3-methylimidazolium cation ([C(2)OHmim](+)) and various anions ([A](-)) of differing H-bond acceptor strength, viz. hexafluorophosphate [PF6](-), tetrafluoroborate [BF4](-), bis-(trifluoromethanesulfonimide) [Tf2N](-), trifluoromethylsulfonate [OTf](-), and trifluoroacetate [TFA](-), was studied by a range of spectroscopic and computational techniques and, in the case of [C(2)OHmim][PF6], by single crystal X-ray diffraction. The first quantitative estimates of the energy (E-HB) and the enthalpy (-Delta H-HB) of H-bonds in bulk ILs were obtained from a theoretical analysis of the solid-state electron-density map of crystalline [C(2)OHmim][PF6] and an analysis of the IR spectra in crystal and liquid samples. E-HB for OH center dot center dot center dot[PF6](-) H-bonds amounts to similar to 3.4-3.8 kcal.mol(-1), whereas weaker H-bonds (2.8-3.1 kcal-mol(-1)) are formed between aromatic C2H group of imidazolium ring and the [PF6](-) anion. The enthalpy of the OH center dot center dot center dot[A](-) H-bonds follows the order: [PF6] (2.4 kcal.mol(-1)) < [BF4] (3.3 kcal.mol(-1)) < [Tf2N] (3.4 kcal-mol(-1))

Ionic liquids doped with I-2, usually resulting in the formation of polyiodide anions, are extensively used as electrolytes and in iodination reactions. Herein, NMR spectroscopy and single-crystal X-ray diffraction were used to rationalize the structures of imidazolium-based polyiodide ionic liquids in the liquid and solid states. Combined, these studies show that extensive interactions between the imidazolium cation and the resulting polyiodide anion are present, which have the net effect of lengthening, polarizing, and weakening the I-I bonds in the anion. This bond weakening rationalizes the high conductivity and reactivity of ionic liquids doped with I-2.

Dinudear metal complexes have emerged as a promising class of anticancer compounds with the ability to cross-link biomolecular targets. Here, we describe two novel series of phosphine-linked dinudear ruthenium(II) p-cyrnene and gold(I) complexes, in which the length of the connecting poly(ethylene glycol) chain has been systematically modified. The impact,Of the multinuclearity, lipophilicity, and linker length on the antiproliferative activity of the compounds-on tumorigenic,(A2780 and A2780cisR) and nonturnorigenic (HEK-293) cell lines was assessed. The dinuclear ruthenium(II) complexes were considerably more cytotoxic than their mononuclear : counterparts, and a correlation between the lipophilicity of the linker and the cytotoxicity was observed, whereas the cytotoxicity of the gold(I) series, is independent of these factors.