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1.
Chem Sci ; 12(11): 3921-3928, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34163661

RESUMO

Drug-induced liver injury (DILI) is an important cause of potentially fatal liver disease. Herein, we report the development of a molecular probe (LW-OTf) for the detection and imaging of two biomarkers involved in DILI. Initially, primary reactive oxygen species (ROS) superoxide (O2˙-) selectively activates a near-infrared fluorescence (NIRF) output by generating fluorophore LW-OH. The C[double bond, length as m-dash]C linker of this hemicyanine fluorophore is subsequently oxidized by reactive nitrogen species (RNS) peroxynitrite (ONOO-), resulting in cleavage to release xanthene derivative LW-XTD, detected using two-photon excitation fluorescence (TPEF). An alternative fluorescence pathway can occur through cleavage of LW-OTf by ONOO- to non-fluorescent LW-XTD-OTf, which can react further with the second analyte O2˙- to produce the same LW-XTD fluorescent species. By combining NIRF and TPEF, LW-OTf is capable of differential and simultaneous detection of ROS and RNS in DILI using two optically orthogonal channels. Probe LW-OTf could be used to detect O2˙- or O2˙- and ONOO- in lysosomes stimulated by 2-methoxyestradiol (2-ME) or 2-ME and SIN-1 respectively. In addition, we were able to monitor the chemoprotective effects of tert-butylhydroxyanisole (BHA) against acetaminophen (APAP) toxicity in living HL-7702 cells. More importantly, TPEF and NIRF imaging confirmed an increase in levels of both O2˙- and ONOO- in mouse livers during APAP-induced DILI (confirmed by hematoxylin and eosin (H&E) staining).

2.
Chem Sci ; 12(7): 2498-2503, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34164016

RESUMO

Reversible enzymatic post-translational modification of the ε-amino groups of lysine residues (e.g. N-acylation reactions) plays an important role in regulating the cellular activities of numerous proteins. This study describes how enzyme catalyzed N-deprotection of lysine residues of non-fluorescent peptide-coumarin probes can be used to generate N-deprotected peptides that undergo spontaneous O- to N-ester transfer reactions (uncatalyzed) to generate a highly fluorescent N-carbamoyl peptide. This enables detection of enzyme catalyzed N-deacetylation, N-demalonylation, N-desuccinylation and N-demethylation reactions activities towards the N-modified lysine residues of these probes using simple 'turn on' fluorescent assays.

3.
Chem Rec ; 21(9): 2585-2600, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33834595

RESUMO

Progress in electroorganic synthesis is linked to innovation of new synthetic reactions with impact on medicinal chemistry and drug discovery and to the desire to minimise waste and to provide energy-efficient chemical transformations for future industrial processes. Paired electrosynthetic processes that combine the use of both anode and cathode (convergent or divergent) with minimal (or without) intentionally added electrolyte or need for additional reagents are of growing interest. In this overview, recent progress in developing paired electrolytic reactions is surveyed. The discussion focuses on electrosynthesis technology with proven synthetic value for the preparation of small molecules. Reactor types are contrasted and the concept of translating light-energy driven photoredox reactions into paired electrolytic reactions is highlighted as a newly emerging trend.

4.
Chem Soc Rev ; 50(1): 9-38, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33169731

RESUMO

Indicator displacement assays (IDAs) offer a unique and innovative approach to molecular sensing. IDAs can facilitate the detection of a range of biologically/environmentally important species, provide a method for the detection of complex analytes or for the determination and discrimination of unknown sample mixtures. These attributes often cannot be achieved by traditional molecular sensors i.e. reaction-based sensors/chemosensors. The IDA pioneers Inouye, Shinkai, and Anslyn inspired researchers worldwide to develop various extensions of this idea. Since their early work, the field of indicator displacement assays has expanded to include: enantioselective indicator displacement assays (eIDAs), fluorescent indicator displacement assays (FIDAs), reaction-based indicator displacement assays (RIAs), DimerDye disassembly assays (DDAs), intramolecular indicator displacement assays (IIDAs), allosteric indicator displacement assay (AIDAs), mechanically controlled indicator displacement assays (MC-IDAs), and quencher displacement assays (QDAs). The simplicity of these IDAs, coupled with low cost, high sensitivity, and ability to carry out high-throughput automation analysis (i.e., sensing arrays) has led to their ubiquitous use in molecular sensing, alongside the other common approaches such as reaction-based sensors and chemosensors. In this review, we highlight the various design strategies that have been used to develop an IDA, including the design strategies for the newly reported extensions to these systems. To achieve this, we have divided this review into sections based on the target analyte, the importance of each analyte and then the reported IDA system is discussed. In addition, each section includes details on the benefit of the IDAs and perceived limitations for each system. We conclude this Tutorial Review by highlighting the current challenges associated with the development of new IDAs and suggest potential future avenues of research.

5.
ACS Cent Sci ; 6(10): 1813-1818, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33145417

RESUMO

A novel photodeactivation strategy for controlling gene expression has been developed based on light-induced activation of cAMP response element binding protein (CREB). Light-induced cleavage of the photoresponsive protecting group of an antagonist of CREB binding protein (CBP) results in photocleaved products with weak binding affinity for CBP. This photodissociation reaction enables protein-protein interactions between CBP and CREB that trigger the formation of a multiprotein transcription complex to turn gene expression "on". This enables irradiation of antagonist-treated HEK293T cells to be used to trigger temporal recovery of CREB-dependent transcriptional activity and endogenous gene expression under photolytic control.

6.
Future Med Chem ; 12(22): 2035-2065, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33169622

RESUMO

As bacteria continue to develop resistance to our existing treatment options, antibiotic innovation remains overlooked. If current trends continue, then we could face the stark reality of a postantibiotic era, whereby routine bacterial infections could once again become deadly. In light of a warning signaled by the WHO, a number of new initiatives have been established in the hope of reinvigorating the antibiotic drug development pipeline. In this perspective, we aim to summarize some of these initiatives and funding options, as well as providing an insight into the predicament that we face. Using clinical trials data, company website information and the most recent press releases, a current update of the antibiotic drug development pipeline is also included.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Desenvolvimento de Medicamentos , Antibacterianos/síntese química , Antibacterianos/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Testes de Sensibilidade Microbiana
7.
Chem Sci ; 11(28): 7329-7334, 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-33033609

RESUMO

In this work, we have developed an ESIPT-based benzimidazole platform (MO-E1 and MO-E2) for the two-photon cell imaging of ONOO- and a potential ONOO--activated theranostic scaffold (MO-E3). Each benzimidazole platform, MO-E1-3, were shown to rapidly detect ONOO- at micromolar concentrations (LoD = 0.28 µM, 6.53 µM and 0.81 µM respectively). The potential theranostic MO-E3 was shown to release the parent fluorophore and drug indomethacin in the presence of ONOO- but unfortunately did not perform well in vitro due to low solubility. Despite this, the parent scaffold MO-E2 demonstrated its effectiveness as a two-photon imaging tool for the ratiometric detection of endogenous ONOO- in RAW264.7 macrophages and rat hippocampus tissue. These results demonstrate the utility of this ESIPT benzimidazole-based platform for theranostic development and bioimaging applications.

8.
Angew Chem Int Ed Engl ; 59(47): 20996-21000, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-32744428

RESUMO

A rationally designed pH-activatable fluorescent probe (pHocas-RIS) has been used to measure localised pH levels in osteocytic lacunae in bone tissue. Conjugation of the moderate bone-binding drug risedronate to a pH-activatable BODIPY fluorophore enables the probe to penetrate osteocytic lacunae cavities that are embedded deep within the bone matrix. After injection of pHocas-RIS, any osteocytic lacunae caused by bone-resorbing osteocytes cause the probe to fluoresce in vivo, thus allowing imaging by intravital two-photon excitation microscopy. This pH responsive probe enabled the visualization of the bone mineralizing activities of acid producing osteocytes in real time, thus allowing the study of their central role in remodeling the bone-matrix in healthy and disease states.


Assuntos
Reabsorção Óssea/diagnóstico , Compostos de Boro/química , Corantes Fluorescentes/química , Imagem Óptica , Osteócitos/citologia , Animais , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Transgênicos , Estrutura Molecular
9.
Chem Soc Rev ; 49(15): 5110-5139, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32697225

RESUMO

In this tutorial review, we will explore recent advances in the construction and application of Förster resonance energy transfer (FRET)-based small-molecule fluorescent probes. The advantages of FRET-based fluorescent probes include: a large Stokes shift, ratiometric sensing and dual/multi-analyte responsive systems. We discuss the underlying energy donor-acceptor dye combinations and emphasise their applications for the detection or imaging of cations, anions, small neutral molecules, biomacromolecules, cellular microenvionments and dual/multi-analyte responsive systems.


Assuntos
Transferência Ressonante de Energia de Fluorescência/métodos , Compostos Inorgânicos/análise , Animais , Transporte Biológico , Melhoramento Biomédico , Técnicas Biossensoriais , Linhagem Celular , Microambiente Celular , Humanos , Íons/análise , Potencial da Membrana Mitocondrial , Microscopia de Fluorescência , Neoplasias/diagnóstico por imagem , Imagem Óptica , Espectrometria de Fluorescência , Propriedades de Superfície
10.
Front Chem ; 8: 389, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32582623

RESUMO

Here, we report a new pentafluoropropanamido rhodamine fluorescent probe (ACS-HNE) that allows for the selective detection of neutrophil elastase (NE). ACS-HNE displayed high sensitivity, with a low limit of detection (<5.3 nM), and excellent selectivity toward elastase over other relevant biological analytes and enzymes. The comparatively poor solubility and cell permeability of neat ACS-HNE was improved by creating an ACS-HNE-albumin complex; this approach allowed for improvements in the in situ visualization of elastase activity in RAW 264.7 cells relative to ACS-HNE alone. The present study thus serves to demonstrate a simple universal strategy that may be used to overcome cell impermeability and solubility limitations, and to prepare probes suitable for the cellular imaging of enzymatic activity in vitro.

11.
Front Chem ; 8: 39, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32154211

RESUMO

The elucidation of biological processes involving reactive oxygen species (ROS) facilitates a better understanding of the underlying progression of non-communicable diseases. Fluorescent probes are a powerful tool to study various ROS and have the potential to become essential diagnostic tools. We have developed a series of coumarin fluorescent probes for the selective and sensitive detection of peroxynitrite (ONOO-), a key ROS. Coumarin based probes exhibit good photostability, large Stokes shift and high quantum yields. The three ratiometric probes all contain a boronate ester motif for the detection of ONOO- and a distinctive organelle targeting group. The study of ONOO- generation in a particular organelle will allow more precise disease profiling. Hence, targeting groups for the mitochondria, lysosome and endoplasmic reticulum were introduced into a coumarin scaffold. The three ratiometric probes displayed sensitive and selective detection of ONOO- over other ROS species. All three coumarin probes were evaluated in murine RAW264.7 macrophages for detection of basal and stimulated ONOO- formation.

12.
J Org Chem ; 85(2): 1208-1215, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31774680

RESUMO

A practically simple three-component chiral derivatization protocol has been developed to determine the enantiopurity of eight S-chiral sulfinamides by 1H and 19F NMR spectroscopic analysis, based on their treatment with a 2-formylphenylboronic acid template and enantiopure pinanediol to afford a mixture of diastereomeric sulfiniminoboronate esters whose diastereomeric ratio is an accurate reflection of the enantiopurity of the parent sulfinamide.

13.
Chem Sci ; 11(32): 8567-8571, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34123116

RESUMO

Reaction-based fluorescent-probes have proven successful for the visualisation of biological species in various cellular processes. Unfortunately, in order to tailor the design of a fluorescent probe to a specific application (i.e. organelle targeting, material and theranostic applications) often requires extensive synthetic efforts and the synthetic screening of a range of fluorophores to match the required synthetic needs. In this work, we have identified Pinkment-OH as a unique "plug-and-play" synthetic platform that can be used to develop a range of ONOO- responsive fluorescent probes for a variety of applications. These include theranostic-based applications and potential material-based/bioconjugation applications. The as prepared probes displayed an excellent sensitivity and selectivity for ONOO- over other ROS. In vitro studies using HeLa cells and RAW 264.7 macrophages demonstrated their ability to detect exogenously and endogenously produced ONOO-. Evaluation in an LPS-induced inflammation mouse model illustrated the ability to monitor ONOO- production in acute inflammation. Lastly, theranostic-based probes enabled the simultaneous evaluation of indomethacin-based therapeutic effects combined with the visualisation of an inflammation biomarker in RAW 264.7 cells.

14.
Chem Commun (Camb) ; 55(100): 15129-15132, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31788680

RESUMO

Here, a reaction-based indicator displacement hydrogel assay (RIA) was developed for the detection of hydrogen peroxide (H2O2) via the oxidative release of the optical reporter Alizarin Red S (ARS). In the presence of H2O2, the RIA system displayed potent biofilm inhibition for Methicillin-resistant Staphylococcus aureus (MRSA), as shown through an in vitro assay quantifying antimicrobial efficacy. This work demonstrated the potential of H2O2-responsive hydrogels containing a covalently bound diol-based drug for controlled drug release.


Assuntos
Antraquinonas/química , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Peróxido de Hidrogênio/química , Staphylococcus aureus Resistente à Meticilina/fisiologia , Antraquinonas/farmacologia , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Hidrogéis/química , Hidrogéis/farmacologia , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Solubilidade
15.
ChemistryOpen ; 8(12): 1407-1409, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31867147

RESUMO

Herein, we report the evaluation and synthesis of a reaction based fluorescent probe DCM-Bpin for the detection of Peroxynitrite (ONOO-). DCM-Bpin exhibits selective fluorescence off-on response for ONOO- over other reactive oxygen species, including H2O2. Moreover, DCM-Bpin is biocompatible and has been used to visualize exogenous ONOO- in HeLa cells.

16.
Front Chem ; 7: 775, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31867305

RESUMO

Two novel drug-conjugates based on a "coumarin linker" have been designed for the synergic release of a therapeutic agent and fluorescent probe for the potential application of theranostics. The drug conjugates; CC-RNS and CI-RNS were designed to be activated by reactive oxygen species or reactive nitrogen species (ROS/RNS). The fluorescence OFF-ON response was triggered by the peroxynitrite-mediated transformation of a boronic acid pinacol ester to a phenol moiety with simultaneous release of the therapeutic agents (Confirmed by HRMS). The limit of detection for peroxynitrite using CC-RNS and CI-RNS was 0.29 and 37.2 µM, respectively. Both CC-RNS and CI-RNS demonstrated the ability to visualize peroxynitrite production thus demonstrating the effectiveness of these probes for use as tools to monitor peroxynitrite-mediated drug release in cancer cell lines.

17.
J Am Chem Soc ; 141(49): 19389-19396, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31773957

RESUMO

Two-photon fluorescence microscopy has become an indispensable technique for cellular imaging. Whereas most two-photon fluorescent probes rely on well-known fluorophores, here we report a new fluorophore for bioimaging, namely azulene. A chemodosimeter, comprising a boronate ester receptor motif conjugated to an appropriately substituted azulene, is shown to be an effective two-photon fluorescent probe for reactive oxygen species, showing good cell penetration, high selectivity for peroxynitrite, no cytotoxicity, and excellent photostability.


Assuntos
Azulenos/química , Corantes Fluorescentes/química , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Espécies Reativas de Nitrogênio/análise , Espécies Reativas de Oxigênio/análise , Azulenos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Limite de Detecção
18.
Acc Chem Res ; 52(9): 2582-2597, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31460742

RESUMO

This Account describes a range of strategies for the development of fluorescent probes for detecting reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive (redox-active) sulfur species (RSS). Many ROS/RNS have been implicated in pathological processes such as Alzheimer's disease, cancer, diabetes mellitus, cardiovascular disease, and aging, while many RSS play important roles in maintaining redox homeostasis, serving as antioxidants and acting as free radical scavengers. Fluorescence-based systems have emerged as one of the best ways to monitor the concentrations and locations of these often very short lived species. Because of the high levels of sensitivity and in particular their ability to be used for temporal and spatial sampling for in vivo imaging applications. As a direct result, there has been a huge surge in the development of fluorescent probes for sensitive and selective detection of ROS, RNS, and RSS within cellular environments. However, cellular environments are extremely complex, often with more than one species involved in a given biochemical process. As a result, there has been a rise in the development of dual-responsive fluorescent probes (AND-logic probes) that can monitor the presence of more than one species in a biological environment. Our aim with this Account is to introduce the fluorescent probes that we have developed for in vitro and in vivo measurement of ROS, RNS, and RSS. Fluorescence-based sensing mechanisms used in the construction of the probes include photoinduced electron transfer, intramolecular charge transfer, excited-state intramolecular proton transfer (ESIPT), and fluorescence resonance energy transfer. In particular, probes for hydrogen peroxide, hypochlorous acid, superoxide, peroxynitrite, glutathione, cysteine, homocysteine, and hydrogen sulfide are discussed. In addition, we describe the development of AND-logic-based systems capable of detecting two species, such as peroxynitrite and glutathione. One of the most interesting advances contained in this Account is our extension of indicator displacement assays (IDAs) to reaction-based indicator displacement assays (RIAs). In an IDA system, an indicator is allowed to bind reversibly to a receptor. Then a competitive analyte is introduced into the system, resulting in displacement of the indicator from the host, which in turn modulates the optical signal. With an RIA-based system, the indicator is cleaved from a preformed receptor-indicator complex rather than being displaced by the analyte. Nevertheless, without a doubt the most significant result contained in this Account is the use of an ESIPT-based probe for the simultaneous sensing of fibrous proteins/peptides AND environmental ROS/RNS.


Assuntos
Corantes Fluorescentes/química , Espécies Reativas de Nitrogênio/análise , Espécies Reativas de Oxigênio/análise , Enxofre/análise , Fluorescência , Corantes Fluorescentes/síntese química , Estrutura Molecular
20.
Front Chem ; 7: 255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119120

RESUMO

A long wavelength TCF-based fluorescent probe (TCF-ALP) was developed for the detection of alkaline phosphatase (ALP). ALP-mediated hydrolysis of the phosphate group of TCF-ALP resulted in a significant fluorescence "turn on" (58-fold), which was accompanied by a colorimetric response from yellow to purple. TCF-ALP was cell-permeable, which allowed it to be used to image ALP in HeLa cells. Upon addition of bone morphogenic protein 2, TCF-ALP proved capable of imaging endogenously stimulated ALP in myogenic murine C2C12 cells. Overall, TCF-ALP offers promise as an effective fluorescent/colorimetric probe for evaluating phosphatase activity in clinical assays or live cell systems.

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