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[Display omitted] • The SAR profiles of 1,4-naphthoquinones for activating XO were first investigated. • Introduction of electron-donor/acceptor units in the A/B ring improved the effect. • The effect was well predicted using the HOMO-LUMO gap and the binding free energy. • The risk of 1,4-naphthoquinones was evaluated with kinetic data and in vivo exposure. Oral intake of 1,4-naphthoquinones could be a potential risk factor for hyperuricemia and gout via activation of xanthine oxidase (XO). Herein, 1,4-naphthoquinones derived from food and food-borne pollutants were selected to investigate the structure and activity relationship (SAR) and the relative mechanism for activating XO in liver S9 fractions from humans (HLS9) and rats (RLS9). The SAR analysis showed that introduction of electron-donating substituents on the benzene ring or electron-withdrawing substituents on the quinone ring improved the XO-activating effect of 1,4-naphthoquinones. Different activation potential and kinetics behaviors were observed for activating XO by 1,4-naphthoquinones in HLS9/RLS9. Molecular docking simulation and density functional theory calculations showed a good correlation between -LogEC 50 and docking free energy or HOMO-LUMO energy gap. The risk of exposure to the 1,4-naphthoquinones was evaluated and discussed. Our findings are helpful to guide diet management in clinic and avoid adverse events attributable to exposure to food-derived 1,4-naphthoquinones. [ABSTRACT FROM AUTHOR]

The eco–environmental toxicity of the rare metal palladium (Pd) has received extensive attention, thereby requiring simple and practical methods for detecting Pd. Herein, a new probe (HPD) based on dicyanoisophorone dye was designed and synthesized for the detection of Pd. HPD provides several advantages for tracking Pd, including near–infrared (NIR) emission (λ ex = 670 nm, λ em = 700 nm), naked–eye recognition, and comprehensive detection of 0/2/4 valence Pd with good selectivity and anti–interference. The reaction–sensing mechanism of HPD for Pd was further studied using density functional theory calculations. HPD was demonstrated to be a promising tool for the detection of Pd in real water samples, as well as the imaging of Pd in living cells and animals. [Display omitted] • A novel intramolecular charge transfer (ICT) based fluorescence probe was developed to detect palladium (Pd). • Near–infrared (NIR) emission and naked–eye detection of Pd are performed. • The detection mechanism of the probe was verified by experiments and calculations. • The probe can detect Pd in real water samples, living cells and animals. [ABSTRACT FROM AUTHOR]

Biothiols, including homocysteine (Hcy), cysteine (Cys) and reduced glutathione (GSH), play various roles in physiological and pathological processes. Because these biothiols possess similar in structures, it is difficult to discriminate Hcy, Cys and GSH from one another. In this work, a novel fluorescent probe, 4-BrCP , based on coumarin as a fluorophore to discriminate GSH from Hcy and Cys was rationally designed and synthesized in three steps with good total yield. The benzothiazol ring played the role of a fluorescent emission wavelength adjuster, while the ester part served as a fluorescent quencher and reactive sites with Hcy, Cys and GSH. The results of responsive experiment indicated that the probe could discriminate GSH from Hcy and Cys distinctly and exhibited a relatively high fluorescence quantum yield (0.84) and low detection limit (9.8 nM). In addition, the probe 4-BrCP also showed good stability and low toxicity. The reaction mechanism of 4-BrCP with GSH was speculated on according to the LC-MS data. Most importantly, because of the length of the skeletons of Hcy, Cys and GSH, different dynamic fluorescent phenomena were observed. Furthermore, imaging experiments suggested that the probe could be used to monitor GSH in living cells and organisms. [Display omitted] • A novel fluorescent probe based on coumarin was rationally designed and synthesized. • The probe could selectively discriminate GSH from Hcy, Cys, or Hcy/Cys/GSH coexisting condition. • The probe showed a good quantum yield (0.84) and low detection limit (9.8 nM). • The probe could trace endogenous GSH in living cells and organisms. [ABSTRACT FROM AUTHOR]

This study aimed to develop a novel and practical fluorescent method for GSH detection in complex biological samples. To this end, a series of coumarin-based fluorescent probes was designed and synthesized using various aliphatic halogens as the sensing group. By using a new evaluation method of GSH/Cys/Hcy coexisting conditions, the probe with chloropropionate (CBF3) showed a high selectivity, excellent sensitivity, good stability for GSH detection. The reaction mechanism is proposed as nucleophilic substitution/cyclization and intramolecular charge transfer (ICT), which was confirmed by LC-MS and NMR analysis, as well as density functional theory calculations. In addition, CBF3 was demonstrated to be competent not only for the quantitative detection of GSH in real serum samples, but also for sensing GSH changes in different oxidative stress models in living cells and nematodes. This study showed a practical strategy for constructing GSH-specific fluorescent probes, and provided a sensitive tool for real-time sensing of GSH in real biological samples. The findings would greatly facilitate further investigations on GSH-associated clinical diagnosis and biomedical studies. Image 1 • A novel SN 2 -triggered and ICT-based fluorescent probe was developed for sensing GSH. • The reaction mechanism was confirmed by experimental and theoretical investigations. • The probe selectively responded to GSH in the GSH/Cys/Hcy coexisting conditions. • The probe exhibited a low detection limit of 9.2 nM. • The probe could monitor GSH in real serum sample, and in living cells and nematodes. [ABSTRACT FROM AUTHOR]

A novel two-photon pH probe, 3-benzimidazole-7-hydroxycoumarin (BHC), was designed and synthesized based on the structures of hydroxycoumarin and benzimidazole. BHC showed good linearity in the pH ranges of 3.30–5.40 (pKa = 4.20) and 6.50–8.30 (pKa = 7.20) at a maximum emission wavelength of 480 nm. BHC in acidic and alkaline media could be distinguished by an obvious spectral shift of the maximum absorption wavelength from 390 nm to 420 nm. In addition, BHC was well localized to mitochondria and successfully applied to one-photon and two-photon imaging of pH changes in the mitochondria of HeLa cells. The findings presented herein suggest that BHC can serve as an excellent fluorescent probe for selectively sensing mitochondrial pH changes with remarkable photostability and low cytotoxicity. Unlabelled Image • A new fluorescent probe for one- and two-photon sensing of pH was developed. • The probe responded sensitively and selectively to pH changes within 3.0–6.0 (pKa = 4.20) and 6.0–9.0 (pKa = 7.20). • The probe was successfully applied for monitoring and imaging of mitochondrial pH in living cells. [ABSTRACT FROM AUTHOR]

Compared with coumarin, 7-hydroxycoumarin could serve as a better hit for developing CYP2A6 inhibitors. In this study, a series of 7-hydroxycoumarin and its structural analogues were collected to study their structure-activity relationship (SAR) and isoform selectivity for inhibiting CYP2A6. All tested coumarins except a C4 phenyl derivative (11) showed higher inhibitory activities for CYP2A6 over the other CYP isoforms, including CYP1A2, CYP2D6, CYP2E1, CYP3A4, CYP2C8, and CYP2C9. Of these coumarins, 6,7-dihydroxycoumarin (1) and 7,8-dihydroxycoumarin (9) were found to be potent inhibitors of CYP2A6 with IC 50 / K i value of 0.39/0.25 and 4.61/3.02 μM, respectively, compared to methoxalen as positive control (IC 50 / K i = 0.43/0.26 μM). In contrast, other coumarins showed low or decreased CYP2A6-inhibiting activities. SAR analysis showed that hydroxy groups might be important for CYP2A6 inhibition, and the rank order of sites for hydroxy substitution was C6 > C7 > C8. In addition, either hydrophobic or hydrophilic substituents introduced into C4, C6 and C8 led to a reduction in CYP2A6-inhibiting activity, and the degree of influence was dependent on the size and electrical charge of substituents. Furthermore, inhibition kinetic analysis and docking simulations demonstrated that the 8- O -glucosylated coumarin derivative (17) exhibited noncompetitive inhibition against CYP2A6, while competitive inhibition patterns were noted for the other tested coumarins. The mechanisms underlying the inhibitors binding to CYP2A6 were further investigated by molecular docking study. The findings presented herein are very helpful for developing highly selective and more potent CYP2A6 inhibitors. Unlabelled Image [ABSTRACT FROM AUTHOR]