Oxidative Stress in Cancer Therapy: Friend or Enemy?

Excessive cellular oxidative stress is widely perceived as a key factor in pathophysiological conditions and cancer development. Healthy cells use several mechanisms to maintain intracellular levels of reactive oxygen species (ROS) and overall redox homeostasis to avoid damage to DNA, proteins, and lipids. Cancer cells, in contrast, exhibit elevated ROS levels and upregulated protective antioxidant pathways. Counterintuitively, such elevated oxidative stress and enhanced antioxidant defence mechanisms in cancer cells provide a therapeutic opportunity for the development of drugs with different anticancer mechanisms of action (MoA). In this review, oxidative stress and the role of ROS in cells are described. The tumour-suppressive and tumour-promotive functions of ROS are discussed, and these two different therapeutic strategies (increasing or decreasing ROS to fight cancer) are compared. Clinically approved drugs with demonstrated oxidative stress anticancer MoAs are highlighted followed by description of examples of metal-based anticancer drug candidates causing oxidative stress in cancer cells via novel MoAs.

Anticancer Water-Soluble Organoruthenium Complexes: Synthesis and Preclinical Evaluation.

The synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate-based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non-small-cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18-electron complexes were designed with four water-soluble phosphine ligands to increase the water-solubility character of the corresponding electron-deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine-3,3',3''-trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16-electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on reactive oxygen species (ROS) production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay.

Synthesis, Characterisation and In Vitro Anticancer Activity of Catalytically Active Indole-Based Half-Sandwich Complexes.

The synthesis, characterisation and evaluation of the in vitro cytotoxicity of four indole-based half-sandwich metal complexes towards two ovarian cancer cell lines (A2780 and A2780cisR) and one normal prostate cell line (PNT2) are presented herein. Although capable of inducing catalytic oxidation of NADH and able to reduce NAD+ with high turnover frequencies, in cells and in the presence of sodium formate, these complexes also strongly interact with biomolecules such as glutathione. This work highlights that efficient out-of-cells catalytic activity might lead to higher reactivity towards biomolecules, thus inhibiting the in-cells catalytic processes.

Effect of Temperature on the Nucleation and Growth of Precious Metal Nanocrystals.

Understanding the effect of physical parameters (e.g., temperature) on crystallisation dynamics is of paramount importance for the synthesis of nanocrystals of well-defined sizes and geometries. However, imaging nucleation and growth is an experimental challenge owing to the resolution required and the kinetics involved. Here, by using an aberration-corrected transmission electron microscope, we report the fabrication of precious metal nanocrystals from nuclei and the identification of the dynamics of their nucleation at three different temperatures (20, 50, and 100 °C). A fast, and apparently linear, acceleration of the growth rate is observed against increasing temperature (78.8, 117.7, and 176.5 pm min-1 , respectively). This work appears to be the first direct observation of the effect of temperature on the nucleation and growth of metal nanocrystals.

Self-Assembly of Temperature-Responsive Protein-Polymer Bioconjugates.

We report a simple temperature-responsive bioconjugate system comprising superfolder green fluorescent protein (sfGFP) decorated with poly[(oligo ethylene glycol) methyl ether methacrylate] (PEGMA) polymers. We used amber suppression to site-specifically incorporate the non-canonical azide-functional amino acid p-azidophenylalanine (pAzF) into sfGFP at different positions. The azide moiety on modified sfGFP was then coupled using copper-catalyzed "click" chemistry with the alkyne terminus of a PEGMA synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. The protein in the resulting bioconjugate was found to remain functionally active (i.e., fluorescent) after conjugation. Turbidity measurements revealed that the point of attachment of the polymer onto the protein scaffold has an impact on the thermoresponsive behavior of the resultant bioconjugate. Furthermore, small-angle X-ray scattering analysis showed the wrapping of the polymer around the protein in a temperature-dependent fashion. Our work demonstrates that standard genetic manipulation combined with an expanded genetic code provides an easy way to construct functional hybrid biomaterials where the location of the conjugation site on the protein plays an important role in determining material properties. We anticipate that our approach could be generalized for the synthesis of complex functional materials with precisely defined domain orientation, connectivity, and composition.

Complementary light scattering and synchrotron small-angle X-ray scattering studies of the micelle-to-unimer transition of polysulfobetaines.

AB and ABA di- and triblock copolymers where A is the hydrophilic poly(oligoethylene glycol methacrylate) (POEGMA) block and B is a thermo-responsive sulfobetaine block [2-(methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide (PDMAPS) were synthesised by aqueous RAFT polymerisation with narrow dispersity (DM ≤ 1.22), as judged by aqueous SEC analysis. The di- and triblock copolymers self-assembled in salt-free water to form micelles with a PDMAPS core and the self-assembly of these polymers was explored by SLS and TEM analysis. The micelles were shown, by DLS analysis, to undergo a micelle-to-unimer transition at a critical temperature, which was dependent upon the length of the POEGMA block. Increasing the length of the third, POEGMA, block decreased the temperature at which the micelle-to-unimer transition occurred as a result of the increased hydrophilicity of the polymer. The dissociation of the micelles was further studied by SLS and synchrotron SAXS. SAXS analysis revealed that the micelle dissociation began at temperatures below that indicated by DLS analysis and that both micelles and unimers coexist. This highlights the importance of using multiple complementary techniques in the analysis of self-assembled structures. In addition the micelle-to-unimer morphology transition was employed to encapsulate and release a hydrophobic dye, Nile Red, as shown by fluorescence spectroscopy.

Designing supramolecular liquid-crystalline hybrids from pyrenyl-containing dendrimers and arene ruthenium metallacycles.

The association of the arene ruthenium metallacycle [Ru4(p-cymene)4(bpe)2(donq)2][DOS]4 (bpe = 1,2-bis(4-pyridyl)ethylene, donq = 5,8-dioxydo-1,4-naphtoquinonato, DOS = dodecyl sulfate) with pyrenyl-functionalized poly(arylester) dendrimers bearing cyanobiphenyl end-groups is reported. The supramolecular dendritic systems display mesomorphic properties as revealed by polarized optical microscopy, differential scanning calorimetry and small-angle X-ray scattering measurements. The multicomponent nature of the dendrimers and of the corresponding host-guest supramolecules (i.e., end-group mesogens, dendritic core, pyrene unit, aliphatic spacers, and metallacycle) leads to the formation of highly segregated mesophases with a complex multilayered structure due to the tendency of the various constitutive building-blocks to separate in different organized zones. The pyrenyl dendrimers exhibit a multilayered smectic A-like phase, thereafter referred to as LamSmA phase to emphasize this unaccustomed morphology. As for the corresponding Ru4-metallacycle adducts, they self-organize into a multicontinuous thermotropic cubic phase with the Im3̅m space group symmetry. This represents a unique example of liquid-crystalline behavior observed for such large and complex supramolecular host-guest assemblies. Models of their supramolecular organizations within both mesophases are proposed.

Enhancement of cytotoxicity by combining pyrenyl-dendrimers and arene ruthenium metallacages.

Three generations of pyrenyl bis-MPA dendrimers with two different end-groups, acetonide (pyr(Gn)) or alcohol (pyr(Gn-OH)) (n = 1-3), were synthesized, and the pyrenyl group of the dendritic molecules was encapsulated in the arene ruthenium metallacages, [Ru(6)(p-cymene)(6)(OO∩OO)(3)(tpt)(2)](6+) (OO∩OO = 5,8-dioxydo-1,4-naphtaquinonato (donq) [1](6+) and 6,11-dioxydo-5,12-naphtacenedionato (dotq) [2](6+); tpt =2,4,6-tri(pyridin-4-yl)-1,3,5-triazine). The host-guest properties of [guest⊂1](6+) and [guest⊂2](6+) were studied in solution by NMR and UV-vis spectroscopic methods, thus allowing the determination of the affinity constants. Moreover, the cytotoxicity of these water-soluble host-guest systems and the pyrenyl-dendrimers was evaluated on human ovarian cancer cells.

Indole-containing arene-ruthenium complexes with broad spectrum activity against antibiotic-resistant bacteria.

Antimicrobial resistant (AMR) bacteria are emerging and spreading globally, threatening our ability to treat common infectious diseases. The development of new classes of antibiotics able to kill or inhibit the growth of such AMR bacteria through novel mechanisms of action is therefore urgently needed. Here, a new family of indole-containing arene ruthenium organometallic compounds are screened against several bacterial species and drug resistant strains. The most active complex [(p-cym)Ru(O-cyclohexyl-1H-indole-2-carbothioate)Cl] (3) shows growth inhibition and bactericidal activity against different organisms (Acinetobacter baumannii, Mycobacterium abscessus, Mycobacterium tuberculosis, Staphylococcus aureus, Salmonella enterica serovar Typhi and Escherichia coli), demonstrating broad-spectrum inhibitory activity. Importantly, this compound series exhibits low toxicity against human cells. Owing to the novelty of the antibiotic family, their moderate cytotoxicity, and their inhibitory activity against Gram positive, Gram negative and acid-fast, antibiotic resistant microorganisms, this series shows significant promise for further development.

Double targeting of tumours with pyrenyl-modified dendrimers encapsulated in an arene-ruthenium metallaprism.

The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene-ruthenium building blocks and 5,8-dioxido-1,4-naphthoquinonato (donq) bridges, in the presence of pyrenyl-containing dendrimers of different generations (P(0), P(1) and P(2)), affords the triangular prismatic host-guest compounds [P(n)⊂Ru(6)(p-cymene)(6)(tpt)(2)(donq)(3)](6+) ([P(n)⊂1](6+)). The host-guest nature of these systems, with the pyrenyl moiety being encapsulated in the hydrophobic cavity of the cage and the dendritic functional group pointing outwards, was confirmed by NMR spectroscopy ((1)H, 2D and DOSY). The host-guest properties of these systems were studied in solution by NMR and UV/Vis spectroscopic methods, allowing the determination of their affinity constants (K(a)). Moreover, the ability of these water-soluble host-guest systems to carry the pyrenyl-containing dendrimers into cancer cells was evaluated on human ovarian cancer cells. The host-guest systems are all more cytotoxic than the empty cage [1][CF(3)SO(3)](6) (IC(50)≈4 µM), with the most active compound, [P(0)⊂1][CF(3)SO(3)](6), being an order of magnitude more cytotoxic.

Evaluation of the Toxicity of Two Electron-Deficient Half-Sandwich Complexes against Human Lymphocytes from Healthy Individuals.

Electron-deficient half-sandwich complexes are a class of under-studied organometallics with demonstrated potential as metallodrug candidates. This study investigates the effect of two 16-electron organoruthenium complexes ([(p-cym)Ru(benzene-1,2-dithiolato)] (1) and [(p-cym)Ru(maleonitriledithiolate)] (2)) on the cell viability of non-immortalised human lymphocytes from healthy individuals. The genotoxic effects of 1 and 2 in lymphocytes are also investigated by using the Comet and cytokinesis-block micronucleus assays. Gene expression studies were carried out on a panel of genes involved in apoptosis and the DNA damage-repair response. Results show that the two 16-electron complexes do not have significant effect on the cell viability of human lymphocytes from healthy individuals. However, an increase in DNA damage is induced by both compounds, presumably through oxidative stress production.

Concomitant control of mechanical properties and degradation in resorbable elastomer-like materials using stereochemistry and stoichiometry for soft tissue engineering.

Complex biological tissues are highly viscoelastic and dynamic. Efforts to repair or replace cartilage, tendon, muscle, and vasculature using materials that facilitate repair and regeneration have been ongoing for decades. However, materials that possess the mechanical, chemical, and resorption characteristics necessary to recapitulate these tissues have been difficult to mimic using synthetic resorbable biomaterials. Herein, we report a series of resorbable elastomer-like materials that are compositionally identical and possess varying ratios of cis:trans double bonds in the backbone. These features afford concomitant control over the mechanical and surface eroding degradation properties of these materials. We show the materials can be functionalized post-polymerization with bioactive species and enhance cell adhesion. Furthermore, an in vivo rat model demonstrates that degradation and resorption are dependent on succinate stoichiometry in the elastomers and the results show limited inflammation highlighting their potential for use in soft tissue regeneration and drug delivery.

Preclinical Anticancer Activity of an Electron-Deficient Organoruthenium(II) Complex.

Ruthenium compounds have been shown to be promising alternatives to platinum(II) drugs. However, their clinical success depends on achieving mechanisms of action that overcome Pt-resistance mechanisms. Electron-deficient organoruthenium complexes are an understudied class of compounds that exhibit unusual reactivity in solution and might offer novel anticancer mechanisms of action. Here, we evaluate the in vitro and in vivo anticancer properties of the electron-deficient organoruthenium complex [(p-cymene)Ru(maleonitriledithiolate)]. This compound is found to be highly cytotoxic: 5 to 60 times more potent than cisplatin towards ovarian (A2780 and A2780cisR), colon (HCT116 p53+/+ and HCT116 p53-/-), and non-small cell lung H460 cancer cell lines. It shows no cross-resistance and is equally cytotoxic to both A2780 and A2780cisR cell lines. Furthermore, unlike cisplatin, the remarkable in vitro antiproliferative activity of this compound appears to be p53-independent. In vivo evaluation in the hollow-fibre assay across a panel of cancer cell types and subcutaneous H460 non-small cell lung cancer xenograft model hints at the activity of the complex. Although the impressive in vitro data are not fully corroborated by the in vivo follow-up, this work is the first preclinical study of electron-deficient half-sandwich complexes and highlights their promise as anticancer drug candidates.

Correction: Pseudo electron-deficient organometallics: limited reactivity towards electron-donating ligands.

Correction for 'Pseudo electron-deficient organometallics: limited reactivity towards electron-donating ligands' by Anaïs Pitto-Barry et al., Dalton Trans., 2017, 46, 15676-15683.

Influence of boron doping on the dynamics of formation of Os metal nanoclusters on graphitic surfaces.

The fabrication of osmium nanoclusters from single atoms has been studied in real-time on B-doped and B-free graphitic surfaces. The dynamics of nucleation on both surfaces are identified, captured, and reported. The nucleation is ca. 2× faster on B-doped surface compared to the B-free surface (38 pm min-1versus 18 pm min-1), suggesting osmium-boron interactions within the nanomaterials.

Anticancer Activity of Electron-Deficient Metal Complexes against Colorectal Cancer in†vitro Models.

An evaluation of the in vitro cytotoxicity of nine electron-deficient half-sandwich metal complexes towards two colorectal cancer cell lines (HCT116 p53+/+, HCT116 p53-/-) and one normal prostate cell line (PNT2) is presented herein. Three complexes were found to be equally cytotoxic towards both colorectal cancer cell lines, suggesting a p53-independent mechanism of action. These complexes are 12 to 34× more potent than cisplatin against HCT116 p53+/+ and HCT116 p53-/- cells. Furthermore, they were found to exhibit little or no cytotoxicity towards PNT2 normal cells, with selectivity ratios greater than 50. To gain an insight into the potential mechanisms of action of the most active compounds, their effects on the expression levels of a panel of genes were measured using qRT-PCR against treated HCT116 p53+/+ and HCT116 p53-/- cells, and cell-cycle analysis was carried out.

Controlled Release of Carbon Monoxide from a Pseudo Electron-Deficient Organometallic Complex.

A 16-electron iridium organometallic is reacted with carbon monoxide to form an 18-electron CO-adduct. This CO-adduct is stable for weeks in the solid state, but quickly reverts to its parent 16-e complex in tetrahydrofuran solution, releasing CO(g). Using a simple methodology, we show that this gas can subsequently be used to perform a carbonylation reaction on another molecule.

Schizophrenia: synthetic strategies and recent advances in drug design.

Schizophrenia is a complex and unpredictable mental disorder which affects several domains of cognition and behaviour. It is a heterogeneous illness characterised by positive, negative, and cognitive symptoms, often accompanied by signs of depression. In this tutorial review, we discuss recent progress in understanding the target sites and mechanisms of action of second-generation antipsychotic drugs. Progress in identifying and defining target sites has been accelerated recently by advances in neuroscience, and newly developed agents that regulate signalling by the main excitatory neurotransmitters in the brain are surveyed. Examples of novel molecules for the treatment of schizophrenia in preclinical and clinical development and their industrial sponsors are highlighted.

New Class of Hybrid Materials for Detection, Capture, and "On-Demand" Release of Carbon Monoxide.

Carbon monoxide (CO) is both a substance hazardous to health and a side product of a number of industrial processes, such as methanol steam reforming and large-scale oxidation reactions. The separation of CO from nitrogen (N2) in industrial processes is considered to be difficult because of the similarities of their electronic structures, sizes, and physicochemical properties (e.g., boiling points). Carbon monoxide is also a major poison in fuel cells because of its adsorption onto the active sites of the catalysts. It is therefore of the utmost economic importance to discover new materials that enable effective CO capture and release under mild conditions. However, methods to specifically absorb and easily release CO in the presence of contaminants, such as water, nitrogen, carbon dioxide, and oxygen, at ambient temperature are not available. Here, we report the simple and versatile fabrication of a new class of hybrid materials that allows capture and release of carbon monoxide under mild conditions. We found that carborane-containing metal complexes encapsulated in networks made of poly(dimethylsiloxane) react with CO, even when immersed in water, leading to dramatic color and infrared signature changes. Furthermore, we found that the CO can be easily released from the materials by simply dipping the networks into an organic solvent for less than 1 min, at ambient temperature and pressure, which not only offers a straightforward recycling method, but also a new method for the "on-demand" release of carbon monoxide. We illustrated the utilization of the on-demand release of CO from the networks by carrying out a carbonylation reaction on an electron-deficient metal complex that led to the formation of the CO-adduct, with concomitant recycling of the gel. We anticipate that our sponge-like materials and scalable methodology will open up new avenues for the storage, transport, and controlled release of CO, the silent killer and a major industrial poison.

Structural Determinants of the Stability of Enzyme-Responsive Polyion Complex Nanoparticles Targeting Pseudomonas aeruginosa's Elastase.

Here, we report how the stability of polyion complex (PIC) particles containing Pseudomonas aeruginosa's elastase (LasB) degradable peptides and antimicrobial poly(ethylene imine) is significantly improved by careful design of the peptide component. Three LasB-degradable peptides are reported herein, all of them carrying the LasB-degradable sequence -GLA- and for which the number of anionic amino acids and cysteine units per peptide were systematically varied. Our results suggest that while net charge and potential to cross-link via disulfide bond formation do not have a predictable effect on the ability of LasB to degrade these peptides, a significant effect of these two parameters on particle preparation and stability is observed. A range of techniques has been used to characterize these new materials and demonstrates that increasing the charge and cross-linking potential of the peptides results in PIC particles with better stability in physiological conditions and upon storage. These results highlight the importance of molecular design for the preparation of PIC particles and should underpin the future development of these materials for responsive drug delivery.