Search

The title compound, 2,2′:4,4′′:4′,4′′′-quaterpyridine (Qtpy), C20H14N4, crystallizes in the triclinic P\overline{1} space group and has half of the molecule in the asymmetric unit, corresponding to 4,4′-bipyridine (4,4′-bpy) that serves as the building block for the molecule. C4,4′-bpy—N—C4,4′-bpy and/or N—C4,4′-bpy—C4,4′-bpy bond-angle parameters show that the 4,4′-bpy ligands are highly rigid, displaying values lower than the linear bond angle of 180°. In the crystal, the 4,4′-bpy units are seen to be facing each other in relatively close proximity. The most important interactions on the Hirshfeld Surface of the compound are C—H...N/H...N—C interactions (constituting 10.6% and 7.6% of the total surface).

A dinuclear ruthenium complex completely inhibits the invasive properties of malignant melanoma within a living human skin model.

Following an overview of the approaches and techniques used to acheive super-resolution microscopy, this review presents the advantages supplied by nanoparticle based probes for these applications. The various clases of nanoparticles that have been developed toward these goals are then critically described and these discussions are illustrated with a variety of examples from the recent literature.

In previous studies we have described the therapeutic action of luminescent dinuclear ruthenium(II) complexes based on the tetrapyridylphenazine, tpphz, bridging ligand on pathogenic strains of Escherichia coli and Enterococcus faecalis. Herein, the antimicrobial activity of the complex against pernicious Gram-negative ESKAPE pathogenic strains of Acinetobacter baumannii (AB12, AB16, AB184 and AB210) and Pseudomonas aeruginosa (PA2017, PA_007_IMP and PA_004_CRCN) are reported. Estimated minimum inhibitory concentrations and minimum bactericidal concentrations for the complexes revealed the complex shows potent activity against all A. baumannii strains, in both glucose defined minimal media and standard nutrient rich Mueller-Hinton-II. Although the activity was lower in P. aureginosa, a moderately high potency was observed and retained in carbapenem-resistant strains. Optical microscopy showed that the compound is rapidly internalized by A. baumannii. As previous reports had revealed the complex exhibited no toxicity in Galleria Mellonella up to concentrations of 80 mg/kg, the ability to clear pathogenic infection within this model was explored. The pathogenic concentrations to the larvae for each bacterium were determined to be ≥ 105 for AB184 and ≥ 103 CFU/mL for PA2017. It was found a single dose of the compound totally cleared a pathogenic A. baumannii infection from all treated G. mellonella within 96 hours. Uniquely, in these conditions thanks to the imaging properties of the complex the clearance of the bacteria within the hemolymph of G. mellonella could be directly visualized through both optical and transmission electron microscopy.

Threading intercalators bind DNA with high affinities. Here, we describe single‐molecule studies on a cell‐permeant luminescent dinuclear ruthenium(II) complex that has been previously shown to thread only into short, unstable duplex structures. Using optical tweezers and confocal microscopy, we show that this complex threads and locks into force‐extended duplex DNA in a two‐step mechanism. Detailed kinetic studies reveal that an individual stereoisomer of the complex exhibits the highest binding affinity reported for such a mono‐intercalator. This stereoisomer better preserves the biophysical properties of DNA than the widely used SYTOX Orange. Interestingly, threading into torsionally constrained DNA decreases dramatically, but is rescued on negatively supercoiled DNA. Given the “light‐switch” properties of this complex on binding DNA, it can be readily used as a long‐lived luminescent label for duplex or negatively supercoiled DNA through a unique “load‐and‐lock” protocol., Using single‐molecule optical tweezers and confocal microscopy we perform kinetic analysis of a novel dinuclear ruthenium(II) DNA imaging probe. Reversable binding is observed on relaxed DNA, however on stretching DNA, threading can occur, resulting in high affinity stable binding. Threading is highly stereoisomer specific and dependent on DNA supercoiling state. This DNA probe has exciting potential for DNA structure specific imaging.

The dental restorative material mercury amalgam has been used for centuries and during this time waste disposal methods have developed considerably. This review provides an overview of how mercury is managed in dental clinics, as well as outlining some possible environmental implications that could occur with poor waste management.

Super-resolution microscopy (SRM) has revolutionized the study of cell biology, enabling researchers to visualize cellular structures with nanometric resolution, single-molecule sensitivity, and with multiple colors using conventional fluorophores. SRM is well-suited for volumetric live-cell imaging and helps in extracting quantitative information on spatial distributions. It can be used to estimate the absolute numbers of proteins or other macromolecules or nanostructured material within subcellular compartments, characterize their structures, and their nano/bio interactions. Although a number of recent general reviews on SRM have elaborated its role in chemical and clinical biology, as well as nanomedicine, herein, we provide an overview of the use of luminescent nanocarriers (LNC) in SRM imaging and single-molecule tracking. The role of LNCs in controlling the brightness and stability of emissive states is discussed with a special focus on organelle-specific delivery and how this approach can be utilized to produce novel optical-switched systems. We also discuss the challenges related to the molecular targeting of such material in biological systems. In doing so, we will provide practical guidance for super-resolution imaging in nanomedicine research, its technical challenges, and the opportunities for future advancement.

Amyloid β oligomers (Aβo) are the main toxic species in Alzheimer's disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aβo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aβo binding by a combined 19F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aβo binding to its receptor PrPC in HEK293 cells. They reduced the pFyn levels triggered by Aβo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer's disease pathology, i.e. prion, Aβ and Tau, affecting three different pathways through specific binding to Aβo and are, indeed, promising candidates for further development.

The dinuclear Ru

Cellular uptake, luminescence imaging and antimicrobial activity against clinically relevant methicillin-resistant S. aureus (MRSA) bacteria are reported. The osmium(ii) complexes [Os(N^N)3]2+ (N^N = 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole (12+); 1-benzyl-4-(pyrimidin-2-yl)-1,2,3-triazole (22+); 1-benzyl-4-(pyrazin-2-yl)-1,2,3-triazole (32+)) were prepared and isolated as the chloride salts of their meridional and facial isomers. The complexes display prominent spin-forbidden ground state to triplet metal-to-ligand charge transfer (3MLCT) state absorption bands enabling excitation as low as 600 nm for fac/mer-32+ and observation of emission in aqueous solution in the deep-red/near-IR regions of the spectrum. Cellular uptake studies within MRSA cells show antimicrobial activity for 12+ and 22+ with greater toxicity for the meridional isomers in each case and mer-12+ showing the greatest potency (32 μg mL−1 in defined minimal media). Super-resolution imaging experiments demonstrate binding of mer- and fac-12+ to bacterial DNA with high Pearson's colocalisation coefficients (up to 0.95 using DAPI). Phototoxicity studies showed the complexes exhibited a higher antimicrobial activity upon irradiation with light., Cellular uptake, luminescence imaging and antimicrobial activity of facial and meridional isomers of Os(ii) triazole-based complexes against methicillin-resistant S. aureus, MRSA.

The synthesis of new dinuclear complexes containing linked RuII(dppz) and ReI(dppz) moieties is reported. The photophysical and biological properties of the new complex, which incorporates a N,N'-bis(4-pyridylmethyl)-1,6-hexanediamine tether ligand, are compared to a previously reported RuII/ReI complex linked by a simple dipyridyl alkane ligand. Although both complexes bind to DNA with similar affinities, steady-state and time-resolved photophysical studies reveal that the nature of the linker affects the excited state dynamics of the complexes and their DNA photocleavage properties. Quantum-based DFT calculations on these systems offer insights into these effects. While both complexes are live cells permeant, their intracellular localizations are significantly affected by the nature of the linker. Notably, one of the complexes displayed concentration-dependent localization and possesses photophysical properties that are compatible with SIM and STED nanoscopy. This allowed the dynamics of its intracellular localization to be tracked at super resolutions.

With the aim of developing photostable near-infrared cell imaging probes, a convenient route to the synthesis of heteroleptic OsII complexes containing the Os(TAP)2 fragment is reported. This method was used to synthesize the dinuclear OsII complex, [{Os(TAP)2}2tpphz]4+ (where tpphz = tetrapyrido[3,2-a:2',3'-c:3″,2''-h:2‴,3'''-j]phenazine and TAP = 1,4,5,8- tetraazaphenanthrene). Using a combination of resonance Raman and time-resolved absorption spectroscopy, as well as computational studies, the excited state dynamics of the new complex were dissected. These studies revealed that, although the complex has several close lying excited states, its near-infrared, NIR, emission (λmax = 780 nm) is due to a low-lying Os → TAP based 3MCLT state. Cell-based studies revealed that unlike its RuII analogue, the new complex is neither cytotoxic nor photocytotoxic. However, as it is highly photostable as well as live-cell permeant and displays NIR luminescence within the biological optical window, its properties make it an ideal probe for optical microscopy, demonstrated by its use as a super-resolution NIR STED probe for nuclear DNA.

With the aim of developing a sensitizer for photodynamic therapy, a previously reported luminescent dinuclear complex that functions as a DNA probe in live cells was modified to produce a new iso-structural derivative containing RuII(TAP)2 fragments (TAP = 1,4,5,8-tetraazaphenanthrene). The structure of the new complex has been confirmed by a variety of techniques including single crystal X-ray analysis. Unlike its parent, the new complex displays Ru → L-based 3MLCT emission in both MeCN and water. Results from electrochemical studies and emission quenching experiments involving guanosine monophosphate are consistent with an excited state located on a TAP moiety. This hypothesis is further supported by detailed DFT calculations, which take into account solvent effects on excited state dynamics. Cell-free steady-state and time-resolved optical studies on the interaction of the new complex with duplex and quadruplex DNA show that the complex binds with high affinity to both structures and indicate that its photoexcited state is also quenched by DNA, a process that is accompanied by the generation of the guanine radical cation sites as photo-oxidization products. Like the parent complex, this new compound is taken up by live cells where it primarily localizes within the nucleus and displays low cytotoxicity in the absence of light. However, in complete contrast to [{RuII(phen)2}2(tpphz)]4+, the new complex is therapeutically activated by light to become highly phototoxic toward malignant human melanoma cell lines showing that it is a promising lead for the treatment of this recalcitrant cancer.

Mitochondria act as a prime therapeutic target for the treatment of various diseases and dysfunctional states. In this study, we have demonstrated the proof of concept of surface functionalization for achieving two-photon active mitochondriotropic lanthanide nanorods for higher resolution fluorescence imaging, and thereby, the spectral profile of mitochondria. The presence of Gd in the nanorods also enabled us to utilize this material as a T(1)-T(2) dual-mode contrast reagent for recording magnetic resonance images of the mouse brain.

Auger electron emitter indium-111 demonstrates cancer-selective radiotoxicity and SPECT imaging compatibility when conjugated to a ruthenium(ii) polypyridyl complex., Theranostic radionuclides that emit Auger electrons (AE) can generate highly localised DNA damage and the accompanying gamma ray emission can be used for single-photon emission computed tomography (SPECT) imaging. Mismatched DNA base pairs (mismatches) are DNA lesions that are abundant in cells deficient in MMR (mismatch mediated repair) proteins. This form of genetic instability is prevalent in the MMR-deficient subset of colorectal cancers and is a potential target for AE radiotherapeutics. Herein we report the synthesis of a mismatch DNA binding bis-ruthenium(ii) dipyridophenazine (dppz) complex that can be radiolabelled with the Auger electron emitting radionuclide indium-111 (111In). Greater stabilisation accompanied by enhanced MLCT (metal to ligand charge-transfer) luminescence of both the bis-Ru(dppz) chelator and non-radioactive indium-loaded complex was observed in the presence of a TT mismatch-containing duplex compared to matched DNA. The radioactive construct [111In]In-bisRu(dppz) ([111In][In-2]4+) targets cell nuclei and is radiotoxic towards MMR-deficient human colorectal cancer cells showing substantially less detrimental effects in a paired cell line with restored MMR function. Additional cell line studies revealed that [111In][In-2]4+ is preferentially radiotoxic towards MMR-deficient colorectal cancer cells accompanied by increased DNA damage due to 111In decay. The biodistribution of [111In][In-2]4+ in live mice was demonstrated using SPECT. These results illustrate how a Ru(ii) polypyridyl complex can incorporate mismatch DNA binding and radiometal chelation in a single molecule, generating a DNA-targeting AE radiopharmaceutical that displays selective radiotoxicity towards MMR-deficient cancer cells and is compatible with whole organism SPECT imaging.

Nucleoside polyphosphates (NPPs) are mainly produced in mitochondria and used as a universal energy source for various cellular events. Although numerous fluorescent probes for adenosine triphosphate (ATP) have been reported, they are not ideally suited for live monitoring of the subtle variation of the mitochondrial ATP level. A new coumarin-based fluorescent probe is synthesized, and this reagent is utilized for specific recognition of NPPs in mitochondria by super-resolution microscopy in physiological condition. Detailed 31P NMR studies reveal that the probe, L·Zn(II), binds to NPPs through their pendent phosphate functionalities. Such binding leads to a substantial enhancement in the luminescence intensity of L·Zn(II) + ADP or L·Zn(II) + ATP as compared to L·Zn(II). This—as well as 1H NMR spectroscopy—has enabled us to evaluate the probe’s binding affinities to these NPPs. Structured illumination and wide field fluorescence microscopy confirmed that this physiologically benign reagent is localized wi...

The synthesis of new dinuclear complexes containing linked Ru

BODIPY derivative, SF-1, exclusively shows a fluorescence ON response to HOCl and images endogenously generated HOCl in RAW 264.7 macrophages. Widefield and super resolution structured illumination microscopy images confirm localization in the Golgi complex and lysosomes, and hence specifically detects HOCl generated in these organelles. SF-1 is compatible with 3D-SIM imaging of individual cells.

Selective detection of nitroxyl (HNO), which has recently been identified as a reactive nitrogen species, is a challenging task. We report a BODIPY-based luminescence ON reagent for detection of HNO in aqueous solution and in live RAW 264.7 cells, based on the soft nucleophilicity of the phosphine oxide functionality toward HNO. The probe shows high selectivity to HNO over other reactive oxygen/nitrogen and sulfur species. Luminescence properties of the BODIPY-based chemodosimetric reagent make it an ideal candidate for use as a reagent for super-resolution structured illumination microscopy. The viability of the reagent for biological in vivo imaging application was also confirmed using Artemia as a model.

With the long-term aim of enhancing the binding properties of dinuclear RuII-based DNA light-switch complexes, a series of eight structurally related mono- and dinuclear systems are reported in which the linker of the bridging ligand has been modulated. These tethered systems have been designed to explore issues of steric demand at the binding site and the thermodynamic cost of entropy loss upon binding. An analysis of detailed spectroscopic and isothermal titration calorimetry (ITC) studies on the new complexes reveal that one of the linkers produces a dinuclear systems that binds to duplex DNA with an affinity (Kb > 107 M-1) that is higher than its corresponding monometallic complex and is the highest affinity for a non-threading bis-intercalating metal complex. These studies confirm that the tether has a major effect on the binding properties of dinuclear complexes containing nintercalating units and establishes key design rules for the construction of dinuclear complexes with enhanced

The preparation, spectroscopic characterization, structural study and magnetic investigation of three new complexes of formula [Co(bpcam)2]ClO4·dmso·H2O (1), [Co(bpcam)2]2[Co(NCS)4]·dmso·H2O (2) and [Ni(bpcam)2]·H2O (3) [Hbpcam = bis(2-pyrimidylcarbonyl)amide] are reported. Each bpcam group in 1–3 acts as a tridentate ligand being coordinated to the cobalt(III) (1 and 2)/nickel(II) (3) ions through three nitrogen atoms in a mer-arrangement. Six-coordinate cobalt(III) and nickel(II) occur in 1 and 3 respectively, whereas six-coordinate cobalt(III) and four-coordinate cobalt(II) coexist in 2. Cyclic voltammetry of 1 in acetonitrile shows the occurrence of one quasi reversible CoIII ↔ CoII process. Direct current (dc) variable-temperature magnetic susceptibility measurements on polycrystalline samples of 2 and 3 were carried out in the temperature range 1.9–295 K. The magnetic behaviour of 2 obeys to the zero-field splitting effects (DCo) of the 4A2 ground term of the pseudotetrahedral [Co(NCS)4]2− complex anion. A Curie law for a magnetically isolated nickel(II) ion in the high temperatures domain occurs for 3, the small decrease of χMT below 10 K being due zero-field splitting effects. The analysis of the magnetic susceptibility data of 2 and 3 through the spin Hamiltonian H = DM[Sz2 − S(S + 1)/3] + gMβHS [M = Co(2) and Ni(3)] led to the following set of values: gM = 2.37 (2) and 2.12 (3) and |DM| = 34.7 (2) and 1.72 cm−1 (3).

β-NaYF4:Yb,Gd up-conversion nanoparticles, UCNPs, surface functionalized with suitable targetting peptides function as nontoxic lysosome-specific imaging probes.\ud \ud

Herein we report the separation of the three stereoisomers of the DNA light-switch compound [{Ru(bpy)2}2(tpphz)]4+ (tpphz = tetrapyrido[3,2-a:2',3'-c:3″,2″-h:2‴,3‴-j]phenazine) by column chromatography and the characterization of each stereoisomer by X-ray crystallography. The interaction of these compounds with a DNA octanucleotide d(GCATATCG).d(CGATATGC) has been studied using NMR techniques. Selective deuteration of the bipyridyl rings was needed to provide sufficient spectral resolution to characterize structures. NMR-derived structures for these complexes show a threading intercalation binding mode with slow and chirality-dependent rates. This represents the first solution structure of an intercalated bis-ruthenium ligand. Intriguingly, we find that the binding site selectivity is dependent on the nature of the stereoisomer employed, with Λ RuII centers showing a better intercalation fit.

Although metal-ion-directed self-assembly has been widely used to construct a vast number of macrocycles and cages, it is only recently that the biological properties of these systems have begun to be explored. However, up until now, none of these studies have involved intrinsically photoexcitable self-assembled structures. Herein we report the first metallomacrocycle that functions as an intracellular singlet oxygen sensitizer. Not only does this Ru2 Re2 system possess potent photocytotoxicity at light fluences below those used for current medically employed systems, it offers an entirely new paradigm for the construction of sensitizers for photodynamic therapy.

With the aim of developing a sensitizer for photodynamic therapy, a previously reported luminescent dinuclear complex that functions as a DNA probe in live cells was modified to produce a new iso-structural derivative containing Ru

The synthesis of two new tetracationic mononuclear RuII complexes containing the tetrapyridyl [3,2-a:2',3'-c:3'',2''-h:2''',3'''-j] phenazine ligand in which the uncoordinated site has been converted into a dicationic ethylene-bipyridyldiylium unit is reported. The structure of the complexes is fully assigned through detailed NMR studies and, in one case, through an X-ray crystallography study. Voltammetry, optical spectroscopy and computational studies confirm that the bipyridyldiylium moiety has a low-lying reduction that quenches the 3MLCT-based emission usually observed in such systems. The new complexes interact with DNA in a quite different manner to their dicationic analogues: they both bind to duplex DNA with micromolar affinity through groove binding. These observations are rationalized through a consideration of their structural and electronic properties.

Surface engineering of nanocarriers allows fine-tuning of their interactions with biological organisms, potentially forming the basis of devices for the monitoring of intracellular events or for intracellular drug delivery. In this context, biodegradable nanocarriers or nanocapsules capable of carrying bioactive molecules or drugs into the mitochondrial matrix could offer new capabilities in treating mitochondrial diseases. Nanocapsules with a polymeric backbone that undergoes programmed rupture in response to a specific chemical or enzymatic stimulus with subsequent release of the bioactive molecule or drug at mitochondria would be particularly attractive for this function. With this goal in mind, we have developed biologically benign nanocapsules using polyurethane-based, polymeric backbone that incorporates repetitive ester functionalities. The resulting nanocapsules are found to be highly stable and monodispersed in size. Importantly, a new non-isocyanate route is adapted for the synthesis of these non-isocyanate polyurethane nanocapsules (NIPU). The embedded ester linkages of these capsules' shells have facilitated complete degradation of the polymeric backbone in response to a stimulus provided by an esterase enzyme. Hydrophilic payloads like rhodamine or doxorubicin can be loaded inside these nanocarriers during their synthesis by an interfacial polymerization reaction. The postgrafting of the nanocapsules with phosphonium ion, a mitochondria-targeting receptor functionality, has helped us achieve the site-specific release of the drug. Co-localization experiments with commercial mitotracker green as well as mitotracker deep red confirmed localization of the cargo in mitochondria. Our in vitro studies confirm that specific release of doxorubicin within mitochondria causes higher cytotoxicity and cell death compared to free doxorubicin. Endogenous enzyme triggered nanocapsule rupture and release of the encapsulated dye is also demonstrated in a zebrafish model. The results of this proof-of-concept study illustrate that NIPU nanocarriers can provide a site-specific delivery vehicle and improve the therapeutic efficacy of a drug or be used to produce organelle-specific imaging studies.

A new physiologically benign and cell membrane permeable BODIPY based molecular probe, MB-Sn, specifically senses intracellular hydrogen polysulfides (H2Sn, n > 1) localized in the endoplasmic reticulum. This reagent is suitable for mapping the intracellular distribution of H2Sn by wide-field as well as super-resolution Structured Illumination Microscopy (SIM).

The DNA binding and cellular localization properties of a new luminescent heterobimetallic Ir(III) Ru(II) tetrapyridophenazine complex are reported. Surprisingly, in standard cell media, in which its tetracationic, isostructural Ru(II) Ru(II) analogue is localized in the nucleus, the new tricationic complex is poorly taken up by live cells and demonstrates no nuclear staining. Consequent cell-free studies reveal that the Ir(III) Ru(II) complex binds bovine serum albumin, BSA, in Sudlow's Site I with a similar increase in emission and binding affinity to that observed with DNA. Contrastingly, in serum-free conditions the complex is rapidly internalized by live cells, where it localizes in cell nuclei and functions as a DNA imaging agent. The absence of serum proteins also greatly alters the cytotoxicity of the complex, where high levels of oncosis/necrosis are observed due to this enhanced uptake. This suggests that simply increasing the lipophilicity of a DNA imaging probe to enhance cellular uptake can be counterproductive as, due to increased binding to serum albumin protein, this strategy can actually disrupt nuclear targeting.

The synthesis of two new Ir(III) complexes which are effectively isostructural with well-established [Ru(NN)2(dppz)](2+) systems is reported (dppz=dipyridophenazine; NN=2,2'-bipyridyl, or 1,10-phenanthroline). One of these Ir(III) complexes is tricationic and has a conventional N6 coordination sphere. The second dicationic complex has a N5C coordination sphere, incorporating a cyclometalated analogue of the dppz ligand. Both complexes show good water solubility. Experimental and computational studies show that the photoexcited states of the two complexes are very different from each other and also differ from their Ru(II) analogues. Both of the complexes bind to duplex DNA with affinities that are two orders of magnitude higher than previously reported Ir(dppz)-based systems and are comparable with Ru(II)(dppz) analogues.

[Ru(phen)2(tpphz)]2+ simultaneously inhibits DNA replication, blocks mitosis and enhances DNA-damaging ionising radiation in oesophageal cancer cells., Substitutionally inert ruthenium(ii) polypyridyl complexes have been developed as DNA intercalating agents yet cellular DNA damage responses to this binding modality are largely unexplored. Here, we show the nuclear-targeting complex [Ru(phen)2(tpphz)]2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) generates rapid and pronounced stalling of replication fork progression in p53-deficient human oesophageal cancer cells. In response, replication stress and double-strand break (DSB) DNA damage response (DDR) pathways are activated and cell proliferation is inhibited by growth arrest. Moreover, mitotic progression is compromised by [Ru(phen)2(tpphz)]2+, where the generation of metaphase chromosome spindle attachment failure results in spindle assembly checkpoint (SAC) activation. This dual mechanism of action results in preferential growth inhibition of rapidly-proliferating oesophageal cancer cells with elevated mitotic indices. In addition to these single-agent effects, [Ru(phen)2(tpphz)]2+ functions as a radiosensitizer with efficiency comparable to cisplatin, which occurs through a synergistic enhancement of DNA damage. These results establish that DNA replication is the target for [Ru(phen)2(tpphz)]2+ and provide the first experimental evidence that ruthenium-based intercalation targets multiple genome integrity pathways in cancer cells, thereby achieving enhanced selectivity compared to existing DNA-damaging agents such as cisplatin.

Using a new mononuclear "building block," for the first time, a dinuclear Ru

The synergistic effect of oxygen, light, and photosensitizer (PS) has found applications in medicine for the treatment of cancer through photodynamic therapy (PDT). Induction of apoptosis to cancerous cells will prevent tumor metastasis that spreads cancer cells to the neighboring organs/tissues. Herein, we report the two apoptotic Ru(II)–polypyridyl complexes that are functionalized with pendant amino acid moieties tyrosine (1) and tryptophan (2), respectively. These two water soluble complexes were found to interact strongly (K1a = (1.18 ± 0.28) × 105 M−1 and K2a = (1.57 ± 0.77) × 105 M−1) with CT-DNA. Isothermal titration calorimetry (ITC) studies revealed that these complexes bind to CT-DNA through an entropically driven process. Both the complexes showed photo-induced cytotoxicity and exhibit apoptotic activity under photo-irradiation conditions. The comet assay indicated that these complexes can damage cellular DNA, which is attributed to the significant build-up of 1O2 level even on irradiation with low intensity light (10 J cm−2, λRange 450–480 nm). This photoinduced DNA damage and apoptosis in A549 cells was induced by reactive oxygen species (ROS) and occurred through up-regulation of apoptotic marker caspase-3. Control experiments under dark conditions revealed an insignificant cytotoxicity towards these cells for two photosensitive molecules.

Herein we describe the DNA binding properties of two new water-soluble ruthenium complexes; experimental and computational data reveal that both complexes display dual emission from MLCT and LLCT excited states. The interaction of the new complexes with DNA was also investigated. Although one of the complexes only binds DNA though groove binding, the second complex has separate ligands capable of groove binding and intercalation. Nevertheless, it was found that both complexes interact with duplex DNA with high affinity. DNA induced distinctive changes in the emission of the complexes; although the groove binding complex only displays a modest increase in emission on binding, the complex that contains the intercalating RuII(dppz) moiety displays a large increase in MLCT-based emission on DNA binding while emission from the LLCT excited state is unaffected. This means that the complex functions as the first ratiometric sensor for DNA.

Detailed studies on the live cell uptake properties of a dinuclear membrane-permeable RuII cell probe show that, at low concentrations, the complex localizes and images mitochondria. At concentrations above ∼20 μM, the complex images nuclear DNA. Because the complex is extremely photostable, has a large Stokes shift, and displays intrinsic subcellular targeting, its compatibility with super-resolution techniques was investigated. It was found to be very well suited to image mitochondria and nuclear chromatin in two color, 2C-SIM, and STED and 3D-STED, both in fixed and live cells. In particular, due to its vastly improved photostability compared to that of conventional SR probes, it can provide images of nuclear DNA at unprecedented resolution.

Techniques concerning postdisaster assessment from remotely sensed images have been studied by different research communities in the past decade. Such an assessment benefits a range of stakeholders, e.g., government organizations, insurance industry, local communities, and individual homeowners. This work explores detailed damage assessment on an individual building basis by utilizing supervised classification. In contrast with previous research efforts in the field, this work attempts at predicting the type of damages such as missing tiles, collapsed rooftop, and presence of holes, gaps, or cavities. Various existing and novel intensity-, edge-, and color-based features are evaluated. Additionally, preprocessing steps that automatically correct photometric and geometric differences are proposed. Furthermore, a study on the reliability of high-resolution aerial imagery in damage interpretation is conducted by comparing results with the assessment of expert volunteers. Results show that the proposed damage detection framework is very effective and performs at a level similar to that of the experts. This paper concludes that the type and extent of damage to individual rooftops can be identified with good accuracy from high-resolution aerial images. It is envisaged that the automated tools presented in this paper would play a significant role in rapid posthurricane damage estimation and in helping to better manage rescue and recovery missions.

The interaction with duplex DNA of a small library of structurally related complexes that all contain a d6-metal ion coordinated to either the 2,2′:4,4′′:4′,4′′′-quaterpyridyl ligand or its methylated derivative are reported. This library is made up of a mixture of newly synthesised and previously reported systems. Despite their structural similarities the complexes display an almost 20-fold variation in binding affinities. Although effects due to the overall charge of the complexes are apparent, the differences in binding characteristics are deeper than this; indeed, in a number of cases, changes in overall charge have little effect on binding affinity. Intriguingly, despite interacting with DNA through unfused ring systems, although two of the complexes studied are groove binders, the majority are non-classical intercalators. A rationale for these effects has been obtained through a combination of experimental and computational studies.

This review outlines the synthesis and properties of mono and oligonuclear polypyridyl ruthenium complexes incorporating a range of S 3 and S 4 thiacrown ligands, focusing on the mixed valence complexes that have been produced in these studies. This work has revealed that the chemical, electrochemical, and electronic properties of the metal centers are modulated by the nature of the coordinated thiacrown ligand. In particular the back-bonding properties of the ligands mean that they strongly stabilize the ruthenium(II) state and also produce metal centers that are relatively kinetically labile. These distinctive electronic properties have been exploited in the construction of mixed valence systems with unusual electrochemical properties and also facilitated the self-assembly of oligonuclear molecular architectures with multiple accessible oxidation states. Computational studies on the isovalent and mixed valence complexes reflect the experimental data by indicating that, within a series of S 4 coordinated dinuclear complexes, the properties of the mixed valence state are subtly dependent on the cavity size of the coordinated thiacrown.

Metal-ion-directed self-assembly has been used to construct kinetically inert, water-soluble heterometallic Ru2Re2 hosts that are potential sensors for bioanions. A previously reported metallomacrocycle and a new derivative synthesised by this approach are found to be general sensors for bioanions in water, showing an "off-on" luminescent change that is selective for nucleotides over uncharged nucleobases. Through a change in the ancillary ligands coordinated to the ruthenium centres of the host, an "off-on" sensor has been produced. Whilst this host only shows a modest enhancement in binding affinities for nucleotides relative to the other two host systems, its sensing response is much more specific. Although a distinctive "off-on" luminescence response is observed for the addition of adenosine triphosphosphate (ATP), related structures such as adenine and guanosine triphosphate (GTP) do not induce any emission change in the host. Detailed and demanding DFT studies on the ATP- and GTP-bound host-guest complexes reveal subtle differences in their geometries that modulate the stacking interactions between the nucleotide guests and the ancillary ligands of the host. It is suggested that this change in stacking geometries affects solvent accessibility to the binding pocket of the host and thus leads to observed difference in the host luminescence response to the guests.

The synthesis of a Ru(II) complex incorporating the 3,3′-bipyrazole (bpyz) ligand is reported. Deprotonation of the ligand leads to shifts in both the metal-to-ligand charge transfer (MLCT) band (80 nm) and the RuIII/II oxidation couple (> 750 mV ) of the complex.

The synthesis and characterization of a series of nine new complexes incorporating [Ru(II)Cl([n]aneS(3))] (n = 12,14, 16) metal centers coordinated to redox active catechol ligands is reported. The solid-state structure of one of these complexes has been determined by X-ray crystallography. The redox properties of these complexes have been probed experimentally through absorption spectroscopy, cyclic voltammetry, and spectroelectrochemistry, as well as computationally through density functional theory calculations. These studies reveal that, whereas the tetrachlorocatechol-based complexes are isolated with the dioxolene unit in the catechol form, the rest of the complexes are isolated in the semiquinone oxidation state. It was also found that the Ru(III/II)-based couple for the complexes is dependent on the nature of the thiacrown ligand coordinated to the metal center. A combination of optical and theoretical studies revealed that the absorption spectra of the complexes contain contributions from a variety of charge transfer processes; in the case of the tetrachlorocatechol complexes these transitions include catechol-to-thiacrown ligand-to-ligand charge transfer.

Synthetic methods toward ruthenium(II) complexes incorporating the benzo[i]dipyrido[3,2-a:2',3'-c]phenazine-11,16-quinone ligand, qdppn, are reported. In several cases, it was found that complexes containing coordinated benzo[i]dipyrido[3,2-a:2',3'-c]phenazine, dppn, could be chemically or photochemically oxidized to their qdppn analogues. Since this method was not possible in all the cases, a new, higher yielding, convenient synthesis of qdppn was developed. The crystal structure of the complex [Ru(phen)(2)(qppn)](PF(6))(2) (phen = 1,10-phenanthroline) which was synthesized from free qdppn reveals that a combination of π-π stacking between coordinated phen and qdppn units, as well as anion-ligand hydrogen bonding, define large hexagonal channels which are occupied by anions and solvent molecules. Electrochemical and photophysical studies reveal that the new qdppn-based complexes are not luminescent and, in contrast to their dppn analogues, they are also poor singlet oxygen sensitizers. Time-resolved studies and density functional theory (DFT) calculations indicate that optical properties of the new complexes are due to a short-lived charge separated state involving the quinone moiety of qdppn. The DNA binding properties of the new complexes have also been investigated. It was found that they are intercalators, displaying binding affinities which are comparable to their dppn analogues.

Few studies have examined the effects of fisheries capture on wild fish, particularly in the context of evaluating the sustainability of capture and release methods for Pacific salmon (Oncorhynchus spp.) during upriver migration. This study examined the physiological condition, post-release behaviour and survival of adult migrating sockeye salmon (O. nerka) in the Fraser River, British Columbia, Canada. Fish were captured by either beach seine or angling and released immediately, or were captured by angling and released following a 24-h recovery period in a net pen. Before release, all salmon were biopsied or tagged with radio telemetry transmitters. Capture by either angling or beach seine with immediate release resulted in >95% survival 24 h after release, whereas net pen recovery after angling resulted in ∼80% survival. This differential in survival was similarly expressed in the percentage of released fish reaching natal sub-watersheds, with 52.2% and 36.3% of fish immediately released by beach seine and angling reaching natal sub-watersheds, respectively, compared with 2.9% of fish released after angling and net pen recovery. Blood plasma stress indices reflected the 10-fold difference in survival, with a ∼4-fold higher plasma cortisol, a ∼2-fold higher plasma glucose and significantly depressed plasma ions and osmolality relative to fish sampled upon capture. Plasma lactate did not differ among groups. Collectively, these results suggest that a 24 h recovery in net pen following angling failed to promote post-release survival experienced with immediate release after angling or beach seining.

The optical response, binding parameters, and duplex DNA binding mode of water-soluble kinetically inert tetranuclear metallomacrocycles can all be controlled by judicious selection of ancillary ligands.

Reaction of 4-bromomethyl-2,6-bis(pyrazol-1-yl)pyridine with dipicolylamine yields 4-bis(pyrid-2-ylmethyl)aminomethyl-2,6-bis(pyrazol-1-yl)pyridine (L). Treatment of L with [MCl 2 (NCPh) 2 ] (M = Pd, Pt) in the presence of AgPF 6 affords [MCl(L)]PF 6 , whose palladium or platinum centre is bound exclusively by the dipicolylamino moiety of L, as established by NMR spectroscopy. The pendant dipyrazolylpyridine residue in these compounds is complexed by iron(II) to form [Fe{MCl(μ-L)} 2 ][PF 6 ] 4 (M = Pd, 1; M = Pt, 2·nH 2 O). The nitromethane solvate crystal of 1 contains low-spin iron centres at 150 K. However, dried 1 and 2·nH 2 O are predominantly high-spin at room temperature, undergoing very gradual thermal spin transitions upon cooling to ≤ 50 % completeness. The platinum compound also undergoes a thermal spin transition in CD 3 NO 2 solution, with T 1/2 = 253 K.

The interaction of the ethylene-bipyridyldiylium-naphthaphenazine dication, dqdppn, with several hexa- and octanucleotide duplexes has been studied using CD and NMR. Taken together, these studies reveal that with the hexanucleotide, dqdppn intercalates into the terminal base pair, and causes a large twisting of the terminal base pair. In contrast, with all three octanucleotides, dqdppn intercalates more centrally within the sequence. The NMR-derived structures of two of the binding complexes demonstrate that dqdppn intercalates from the major groove in an unusual 'side-on' geometry, rather than threading through the helix. An analysis of these results indicates that the preferred binding site is not sequence-specific, but primarily at the most conformationally flexible DNA step.

A family of coordination complexes has been synthesized, each comprising a ruthenium(II) center ligated by a thiacrown macrocycle, [9]aneS(3), [12]aneS(4), or [14]aneS(4), and a pair of cis-coordinated ligands, niotinamide (nic), isonicotinamide (isonic), or p-cyanobenzamide (cbza), that provide the complexes with peripherally situated amide groups capable of hydrogen bond formation. The complexes [Ru([9]aneS(3))(nic)(2)Cl]PF(6), 1(PF(6)); [Ru([9]aneS(3)) (isonic)(2)Cl]PF(6), 2(PF(6)); [Ru([12]aneS(4))(nic)(2)](PF(6))(2), 3(PF(6))(2); [Ru([12]aneS(4))(isonic)(2)](PF(6))(2), 4(PF(6))(2); [Ru([12]aneS(4)) (cbza)(2)](PF(6))(2), 5(PF(6))(2); [Ru([14]aneS(4))(nic)(2)](PF(6))(2), 6(PF(6))(2); [Ru([14]aneS(4))(isonic)(2)](PF(6))(2), 7(PF(6))(2); and [Ru([14]aneS(4))(cbza)(2)](PF(6))(2), 8(PF(6))(2) have been characterized by NMR spectroscopy, mass spectrometry, and elemental analysis. UV/visible spectroscopy shows that each complex exhibits an intense high-energy band (230-255 nm) assigned to a pi-pi* transition and a lower energy band (297-355 nm) assigned to metal-to-ligand charge-transfer transitions. Electrochemical studies indicate good reversibility for the oxidations of complexes with nic and isonic ligands (|I(a)/I(c)| = 1; DeltaEp100 mV), In contrast, complexes 5 and 8, which incorporate cbza ligands, display oxidations that are not fully electrochemically reversible (|I(a)/I(c)| = 1, DeltaEpor = 100 mV). Metal-based oxidation couples between 1.32 and 1.93 V versus Ag/AgCl can be rationalized in term of the acceptor capabilities of the thiacrown ligands and the amide-bearing ligands, as well as the pi-donor capacity of the chloride ligands in compounds 1 and 2. The potential to use these electroactive metal complexes as building blocks for hydrogen-bonded crystalline materials has been explored. Crystal structures of compounds 1(PF(6)).H(2)O, 1(BF(4)).2H(2)O, 2(PF(6)), 3(PF(6))(2), 6(PF(6))(2)CH(3)NO(2), and 8(PF(6))(2) are reported. Four of the six form amide-amide N-H...O hydrogen bonds leading to networks constructed from amide C(4) chains or tapes containing R(2)(2) (8) hydrogen-bonded rings. The other two, 2(PF(6)) and 8(PF(6)), form networks linked through amide-anion N-H...F hydrogen bonds. The role of counterions and solvent in interrupting or augmenting direct amide-amide network propagation is explored, and the systematic relationship between the hydrogen-bonded networks formed across the series of structures is presented, showing the relationship between chain and tape arrangements and the progression from 1D to 2D networks. The scope for future systematic development of electroactive tectons into network materials is discussed.

Three new copper(II) complexes of formulae [Cu(bpcam)(tcm)(H2O)] · 2H2O (1), [Cu(bpcam)(tcm)(H2O)] (2) and [Cu(bpcam)(tcm)]n (3) [bpcam = bis(2-pyrimidylcarbonyl)amidate and tcm = tricyanomethanide] have been prepared and their structures determined by single crystal X-ray diffraction. Complexes 1 and 2 are mononuclear species where each copper atom is five-coordinated in a somewhat distorted square pyramidal environment with a tridentate bpcam ligand and a terminally bound tcm group building the basal plane and a water molecule in the apical position. Compound 3 is a uniform copper(II) chain where the [Cu(bpcam)]+ units are connected through single μ-1,5-tcm bridges which link one equatorial position at one copper atom with the apical position of the adjacent copper. The intrachain meal–metal separation in 3 is 7.678(2) A. Magnetic susceptibility measurements of 3 in the temperature range 1.9–295 K show the occurrence of a weak intrachain antiferromagnetic interaction [J = −0.39 cm−1 with the Hamiltonian being defined as H ˆ = - J ∑ i S ˆ i · S ˆ i + 1 ]. This value of the magnetic coupling is analyzed through simple orbital symmetry considerations and compared with those observed through this bridge in other magneto-structurally characterized copper(II) complexes.