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1.
Molecules ; 25(10)2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32455529

RESUMO

The histone deacetylase (HDAC) enzymes have emerged as an important class of molecular targets in cancer therapy, with five inhibitors in clinical use. Recently, it has been shown that a lack of selectivity between the 11 Zn-dependent HDAC isoforms may lead to unwanted side-effects. In this paper, we show that piano stool Ru complexes can act as HDAC inhibitors, and variation in the capping arene leads to differences in HDAC isoform selectivity.

2.
Ecology ; 101(8): e03072, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32298472

RESUMO

Some invasive plant species rapidly evolve greater size and/or competitive ability in their nonnative ranges. However, it is not well known whether these traits transfer back to the native range, or instead represent genotype-by-environment interactions where traits are context specific to communities in the new range where the evolution occurred. Insight into transferability vs. context specificity can be tested using experiments performed with individuals from populations from the native and nonnative ranges of exotic invasive species. Using a widespread invasive plant species in Europe, Solidago gigantea, we established reciprocal common garden experiments in the native range (Montana, North America; n = 4) and the nonnative range (Hungary, Europe; n = 4) to assess differences in size, vegetative shoot number, and herbivory between populations from the native and nonnative ranges. In a greenhouse experiment, we also tested whether the inherent competitive ability of genotypes from 15 native and 15 invasive populations differed when pitted against 11 common native North American competitors. In common gardens, plants from both ranges considered together produced five times more biomass, grew four times taller, and developed five times more rhizomes in the nonnative range garden compared to the native range garden. The interaction between plant origin and the common garden location was highly significant, with plants from Hungary performing better than plants from Montana when grown in Hungary, and plants from Montana performing better than plants from Hungary when grown in Montana. In the greenhouse, there were no differences in the competitive effects and responses of S. gigantea plants from the two ranges when grown with North American natives. Our results suggest that S. gigantea might have undergone rapid evolution for greater performance abroad, but if so, this response does not translate to greater performance at home.

3.
Nat Commun ; 11(1): 1676, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245991

RESUMO

Circular polarisation luminescence (CPL) emission spectroscopy is a powerful tool for probing the fundamental chiroptical features of optically emissive chiral molecular systems. However, uptake of CPL spectroscopy has been impeded by the limitations of conventional scanning monochromator (SM) CPL spectrometers, which are costly to acquire and maintain, and typically require tens of minutes to acquire a typical CPL spectrum. Here, we demonstrate a design of CPL spectrometer which uses rapid readout solid state (SS) spectrometer detectors and a dual channel optical layout to acquire CPL spectra in as little as 10 milliseconds. We validate and demonstrate equivalent CPL measurement by measuring CPL spectra of two reference europium(III) complexes. Further, we demonstrate time-gated CPL acquisition, enabling long-lived CPL luminescence to be distinguished from short-lived emission of other fluorescent species. We anticipate that SS-CPL spectrometers will enable flexible, rapid, and relatively low-cost CPL spectroscopy for diverse applications.

4.
ACS Appl Mater Interfaces ; 12(12): 13657-13670, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32091877

RESUMO

Light-activated molecular nanomachines (MNMs) can be used to drill holes into prokaryotic (bacterial) cell walls and the membrane of eukaryotic cells, including mammalian cancer cells, by their fast rotational movement, leading to cell death. We examined how these MNMs function in multicellular organisms and investigated their use for treatment and eradication of specific diseases by causing damage to certain tissues and small organisms. Three model eukaryotic species, Caenorhabditis elegans, Daphnia pulex, and Mus musculus (mouse), were evaluated. These organisms were exposed to light-activated fast-rotating MNMs and their physiological and pathological changes were studied in detail. Slow rotating MNMs were used to control for the effects of rotation rate. We demonstrate that fast-rotating MNMs caused depigmentation and 70% mortality in C. elegans while reducing the movement as well as heart rate and causing tissue damage in Daphnia. Topically applied light-activated MNMs on mouse skin caused ulceration and microlesions in the epithelial tissue, allowing MNMs to localize into deeper epidermal tissue. Overall, this study shows that the nanomechanical action of light-activated MNMs is effective against multicellular organisms, disrupting cell membranes and damaging tissue in vivo. Customized MNMs that target specific tissues for therapy combined with spatial and temporal control could have broad clinical applications in a variety of benign and malignant disease states including treatment of cancer, parasites, bacteria, and diseased tissues.

5.
ACS Appl Mater Interfaces ; 12(1): 410-417, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31815419

RESUMO

Recently, synthetic molecular nanomachines (MNMs) that rotate unidirectionally in response to UV light excitation have been used to produce nanomechanical action on live cells to kill them through the drilling of holes in their cell membranes. In the work here, visible-light-absorbing MNMs are designed and synthesized to enable nanomechanical activation by 405 nm light, thereby using a wavelength of light that is less phototoxic than the previously employed UV wavelengths. Visible-light-absorbing MNMs that kill pancreatic cancer cells upon response to light activation are demonstrated. Evidence is presented to support the conclusion that MNMs do not kill cancer cells by the photothermal effect when used at low optical density. In addition, MNMs suppress the formation of reactive oxygen species, leaving nanomechanical action as the most plausible working mechanism for cell killing under the experimental conditions.

6.
Bioconjug Chem ; 31(2): 229-240, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31751113

RESUMO

The syntheses and photophysical behavior of nine strongly luminescent nonadentate Eu(III) complexes are reported. Each complex is based on N-functionalized 1,4,7-triazacyclononane, and linkage to other groups or targeting vectors can occur either via amide bond formation to a coordinated pyridine p-aminopropyl group or via a nucleophilic substitution reaction involving thiol attack on a metal coordinated p-nitropyridyl moiety. Evidence is presented in favor of the latter conjugation strategy, as parallel work with maleimide conjugates was complicated or compromised by the propensity to undergo post-conjugation thiol exchange or succinimide ring hydrolysis reactions. Confocal microscopy and spectral imaging studies revealed that the peptide conjugate of AcCFFKDEL was found to localize selectively in the endoplasmic reticulum of mouse fibroblast cells, whereas the related maleimide conjugate was only observed in cellular lysosomes.

7.
ACS Nano ; 13(12): 14377-14387, 2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31815423

RESUMO

Multidrug resistance in pathogenic bacteria is an increasing problem in patient care and public health. Molecular nanomachines (MNMs) have the ability to open cell membranes using nanomechanical action. We hypothesized that MNMs could be used as antibacterial agents by drilling into bacterial cell walls and increasing susceptibility of drug-resistant bacteria to recently ineffective antibiotics. We exposed extensively drug-resistant Klebsiella pneumoniae to light-activated MNMs and found that MNMs increase the susceptibility to Meropenem. MNMs with Meropenem can effectively kill K. pneumoniae that are considered Meropenem-resistant. We examined the mechanisms of MNM action using permeability assays and transmission electron microscopy, finding that MNMs disrupt the cell wall of extensively drug-resistant K. pneumoniae, exposing the bacteria to Meropenem. These observations suggest that MNMs could be used to make conventional antibiotics more efficacious against multi-drug-resistant pathogens.

8.
Chem Commun (Camb) ; 55(94): 14115-14118, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31697292

RESUMO

The enantiomers of [EuL3]·3Cl, an analogue of Eu:BPEPC with a lowered energy excitation wavelength, serve as effective reference complexes for the calibration of circularly polarised luminescence (CPL) spectrometers.

9.
Inorg Chem ; 58(19): 12506-12510, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31490674

RESUMO

One-step cyclization of a tetraazamacrocycle 5 with 70% yield in a 25-g scale was performed. Its chiral DOTA derivatives, L4, has ∼93% of TSAP coordination isomer in its Eu(III) and Yb(III) complexes in aqueous solution. [GdL4]5- exhibits a high relaxivity, making it a promising and efficient MRI contrast agent. High luminescence dissymmetry factor (glum) values of 0.285 (ΔJ = 1) for [TbL3]- and 0.241 (ΔJ = 1) for [TbL4]5- in buffer solutions were recorded.

10.
ACS Nano ; 13(6): 6813-6823, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31117378

RESUMO

Using two-photon excitation (2PE), molecular nanomachines (MNMs) are able to drill through cell membranes and kill the cells. This avoids the use of the more damaging ultraviolet light that has been used formerly to induce this nanomechanical cell-killing effect. Since 2PE is inherently confocal, enormous precision can be realized. The MNMs can be targeted to specific cell surfaces through peptide addends. Further, the efficacy was verified through a controlled opening of synthetic bilayer vesicles using the 2PE excitation of MNM that had been trapped within the vesicles.

11.
J Fluoresc ; 29(1): 255-263, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30588577

RESUMO

In this work we demonstrate that time domain techniques can be used successfully to monitor realtively weak modulations of the fluorescence in sensing applications. The metal sensing complex Newport Green DCF™ can detect selected transition metals in vivo as well as in vitro. Incremental addition of Ni and/or Zn (in vitro) lead to a substantial reduction in the yield of the fast component in a bi-exponential fluorescence decay (τ1 = 150-250 ps) from 60% to 30-35%. This is rationalised as an inhibition of intra-molecular electron transfer in the NPG sensing complex due to metal complexation. In order to explore this effect in cellulo, NIH 3 T3 mouse skin fibroplast cells were pre-incubated with set levels of Ni and Zn, at a constant concentration of NPG. The fluorescence modulation in cellullo was subsequently studied employing both time-resolved fluorescence microscopy and confocal fluorescence microscopy. In correlation with the in vitro observations, similar effects were observed on the fluorescence decay in cellulo.


Assuntos
Complexos de Coordenação/química , Corantes Fluorescentes/química , Elementos de Transição/química , Animais , Células Cultivadas , Camundongos , Microscopia de Fluorescência , Células NIH 3T3 , Espectrometria de Fluorescência
12.
Inorg Chem ; 58(1): 495-505, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30561998

RESUMO

An in-depth study of the interaction of a trinuclear terbium(III)-dizinc(II) complex with an array of nucleotides differing in the type of nucleobase and number of phosphate groups, as well as cyclic versus acyclic variants, is presented. The study examined the nature of the interaction and the efficiency at which guanine was able to sensitize terbium(III) luminescence. Competitive binding and titration studies were performed to help establish the nature/mode of the interactions. These established that (1) interaction occurs by the coordination of phosphate groups to zinc(II) (in addition to uridine in the case of uridine monophosphate), (2) acyclic nucleotides bind more strongly than cyclic counterparts because of their higher negative charge, (3) guanine-containing nucleotides are able to sensitize terbium(III) luminescence with the efficiency of sensitization following the order guanosine monophosphate (GMP) > guanosine diphosphate > guanosine triphosphate because of the mode of binding, and (4) nucleoside monophosphates bind to a single zinc(II) ion, whereas di- and triphosphates appear to bind in a bridging mode between two host molecules. Furthermore, it has been shown that guanine is a sensitizer of terbium(III) luminescence. On the basis of the ability of GMP to effectively sensitize terbium(III)-based luminescence while cyclic GMP (cGMP) does not, the complex has been utilized to monitor the catalytic conversion of cGMP to GMP by a phosphodiesterase enzyme in real time using time-gated luminescence on a benchtop fluorimeter. The complex has the potential to find broad application in monitoring the activity of enzymes that process nucleotides (co)substrates, including high-throughput drug-screening programs.


Assuntos
Complexos de Coordenação/química , Guanosina Monofosfato/química , Diester Fosfórico Hidrolases/análise , Térbio/química , Zinco/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/efeitos da radiação , GMP Cíclico/química , Ensaios Enzimáticos , Luz , Luminescência , Espectrofotometria , Água/química
13.
Chempluschem ; 84(12): 1777, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31943859

RESUMO

Invited for this month's cover are the collaborating groups of Dr. Thomas Just Sørensen at the University of Copenhagen, Denmark and Dr. Robert Pal at Durham University, United Kingdom. The front cover shows the clouds parting for a cell imaged using a thioxanthone-appended EuIII complex. This work shows that lanthanide luminescence can be used in optical bioimaging with microscopes equipped with the common blue laser line. Read the full text of the article at 10.1002/cplu.201900309.

14.
Chempluschem ; 84(12): 1778-1788, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31943860

RESUMO

Bright lanthanide based probes for optical bioimaging must rely on the antenna principle, where the lanthanide-centred excited state is formed by a complex sensitization process. Efficient sensitization of lanthanide-centred emission occurs via triplet states centred on the sensitizing chromophore. Here, the triplet state of thioxanthone chromophores is modulated by extending the π-system. Three thioxanthone chromophores-thioxanthone, benzo[c]thioxanthone, and naphtho[2,3-c]thioxanthone were synthesised and characterised. The triplet state energies and lifetimes is found to change as expected, and two dyes are found to be suitable sensitizers for europium(iii) luminescence. Reactive derivatives of thioxanthone and benzo[c]thioxanthone were prepared and coupled to a 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) lanthanide binding pocket. The photophysics and the performance in optical bioimaging of the resulting europium(iii) complexes were investigated. It is concluded that while the energetics favour efficient sensitization, the solution structure does not. While it was found that the complexes are too lipophilic to be efficient luminescent probes for optical bioimaging, we successfully demonstrated bioimaging using europium(iii) luminescence following 405 nm excitation.

15.
Dalton Trans ; 47(45): 16145-16154, 2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30378619

RESUMO

A series of four emissive europium complexes has been evaluated for the binding of glyphosate in various aqueous media, including river water and grain extracts. Binding selectivity toward inorganic phosphate and bicarbonate was enhanced by measuring samples at pH 5.9, above the pKa of glyphosate itself. The highest affinity was shown with [Eu·L1], which creates an exocyclic tripicolylamine moiety when one pyridine group dissociates from Eu. Glyphosate was bound selectively over dihydrogenphosphate, glycinate, aminomethylphosphonate and the related herbicide glufosinate. The complex was used to measure glyphosate over the range 5 to 50 µM, in river water and grain extracts.

16.
Inorg Chem ; 57(22): 14450-14462, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30383377

RESUMO

Improving the spatial alignment of emitting molecules has long been a goal of organic-light-emitting-diode development to improve device efficiencies and to generate polarized emission. Herein we describe a simple approach employing Sonogashira coupling with alkyne iridium(phenylpyridine)2(acetylacetone) synthons (2-5) to generate eight linear iridium complexes (6-13) with crystallographically determined lengths of up to 5 nm. By embedding these "long" complexes into a polymer matrix and stretching it, an improvement of the polarization ratio of unstretched and stretched films of up to 7.1 times was achieved. Additionally, through the inclusion of "twists" in the complexes, the electronic coupling between the iridium center and substituent was controlled, giving a system where the emission behavior is independent of the length.

17.
Chemistry ; 24(42): 10745-10755, 2018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-29761917

RESUMO

The ability to study cellular metabolism and enzymatic processes involving adenosine triphosphate (ATP) is impeded by the lack of imaging probes capable of signalling the concentration and distribution of intracellular ATP rapidly, with high sensitivity. We report here the first example of a luminescent lanthanide complex capable of visualizing changes in the concentration of ATP in the mitochondria of living cells. Four cationic europium(III) complexes [Eu.1-4]+ have been synthesized and their binding capabilities towards nucleoside polyphosphate anions examined in aqueous solution at physiological pH. Complexes [Eu.1]+ and [Eu.3]+ bearing hydrogen bond donor groups in the pendant arms showed excellent discrimination between ATP, ADP and monophosphate species. Complex [Eu.3]+ showed relatively strong binding to ATP (logKa =5.8), providing a rapid, long-lived luminescent signal that enabled its detection in a highly competitive aqueous medium containing biologically relevant concentrations of Mg2+ , ADP, GTP, UTP and human serum albumin. This EuIII complex responds linearly to ATP within the physiological concentration range (1-5 mm), and was used to continuously monitor the apyrase-catalyzed hydrolysis of ATP to ADP in vitro. We demonstrate that [Eu.3]+ can permeate mammalian (NIH-3T3) cells efficiently and localize to the mitochondria selectively, permitting real-time visualization of elevated mitochondrial ATP levels following treatment with a broad spectrum kinase inhibitor, staurosporine, as well as depleted ATP levels upon treatment with potassium cyanide under glucose starvation conditions.


Assuntos
Trifosfato de Adenosina/metabolismo , Antígenos CD/química , Apirase/química , Európio/química , Íons/química , Mitocôndrias/metabolismo , Trifosfato de Adenosina/química , Animais , Humanos , Luminescência , Mitocôndrias/química
18.
Chem Sci ; 9(4): 1042-1049, 2018 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-29675151

RESUMO

The selective mitochondrial localisation of the Λ enantiomer of three different emissive europium(iii) complexes in NIH 3T3 and MCF7 cells contrasts with the behaviour of the Δ enantiomer, for which a predominant lysosomal localisation was observed by confocal microscopy. In each case, cell uptake occurs via macropinocytosis.

19.
R Soc Open Sci ; 5(3): 171336, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29657751

RESUMO

Structured illumination microscopy is a super-resolution technique used extensively in biological research. However, this technique is limited in the maximum possible resolution increase. Here we report the results of simulations of a novel enhanced multi-spot structured illumination technique. This method combines the super-resolution technique of difference microscopy with structured illumination deconvolution. Initial results give at minimum a 1.4-fold increase in resolution over conventional structured illumination in a low-noise environment. This new technique also has the potential to be expanded to further enhance axial resolution with three-dimensional difference microscopy. The requirement for precise pattern determination in this technique also led to the development of a new pattern estimation algorithm which proved more efficient and reliable than other methods tested.

20.
Chemistry ; 24(28): 7137-7148, 2018 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-29570870

RESUMO

EDTA is widely used as an inhibitor of bacterial growth, affecting the uptake and control of metal ions by microorganisms. We describe the synthesis and characterisation of two symmetrical bis-amide derivatives of EDTA, featuring glycyl or pyridyl substituents: AmGly2 and AmPy2 . Metal ion affinities (logK) have been evaluated for a range of metals (Mg2+ , Ca2+ , Fe3+ , Mn2+ , Zn2+ ), revealing less avid binding compared to EDTA. The solid-state structures of AmGly2 and of its Mg2+ complex have been determined crystallographically. The latter shows an unusual 7-coordinate, capped octahedral Mg2+ centre. The antibacterial activities of the two ligands and of EDTA have been evaluated against a range of health-relevant bacterial species, three Gram negative (Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae) and a Gram positive (Staphylococcus aureus). The AmPy2 ligand is the only one that displays a significant inhibitory effect against K. pneumoniae, but is less effective against the other organisms. AmGly2 exhibits a more powerful inhibitory effect against E. coli at lower concentrations than EDTA (<3 mm) or AmPy2 , but loses its efficacy at higher concentrations. The growth inhibition of EDTA and AmGly2 on mutant E. coli strains with defects in outer-membrane lipopolysaccharide (LPS) structures has been assessed to provide insight into the unexpected behaviour. Taken together, the results contradict the assumption of a simple link between metal ion affinity and antimicrobial efficacy.


Assuntos
Amidas/química , Antibacterianos/química , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Íons/química , Metais/química , Staphylococcus aureus/efeitos dos fármacos , Ligantes
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