Shanghai Key Laboratory of New Drug Design

Laboratory of, China

Shanghai Key Laboratory of New Drug Design

Laboratory of, China
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Tong H.,Shanghai Key Laboratory of New Drug Design | Zhang Y.,Shanghai Key Laboratory of New Drug Design | Ma S.,Shanghai Key Laboratory of New Drug Design | Zhang M.,Shanghai Key Laboratory of New Drug Design | And 4 more authors.
Chinese Chemical Letters | Year: 2017

Hypochlorous acid (HOCl) is one of highly reactive oxygen species (ROS). It is involved in both immune defense against invading microbes and the progression of many diseases including cardiovascular disease and neurodegeneration disorders. It is generated from hydrogen peroxide (H2O2) and chloride ions in the presence of myeloperoxidase in activated neutrophils. To illustrate HOCl's biological functions, fluorescent probes, particularly those fluorescence emissions are in the near-infrared range, are highly needed for in vivo applications. Herein, we reported the design of a pinacol boronate caged near-infrared (NIR) fluorescent probe 1 derived from an Aβ binding fluorophore NIAD-4 for fast and selective detection of HOCl/ClO- over other ROS. Upon exposure to HOCl/ClO-, the pinacol boronate caging group of the probe 1 was quickly converted to electron-donating hydroxyl group, which increased intramolecular charge transfer (ICT) in the excited state and resulted in the red-shift and intensity enhancement of fluorescence emission. The probe bears several unique features: (1) It could be used as either a ratiomatic or turn-on fluorescent probe; (2) Reaction of the caging group boronate with HOCl is very fast and finishes within seconds, which provides the selectivity over H2O2; (3) The NIAD-4 fluorophore provides additional selectivity for detection of HOCl over peroxynitrite. Moreover, the utility of the probe in imaging HOCl/ClO- was demonstrated in in vitro phantom imaging studies using mouse brain homogenate as biological relevant media. © 2017.


Jiao C.-P.,Shanghai Key Laboratory of Functional Materials Chemistry | Ye Y.-J.,Shanghai Key Laboratory of New Drug Design | Ye Y.-J.,East China University of Science and Technology | Zhang Y.,Shanghai First Peoples Hospital | And 3 more authors.
Chinese Journal of Pharmacology and Toxicology | Year: 2013

OBJECTIVE: To elucidate silica nanoparticle-induced cytotoxicity and its mechanism by investigating the effect of silica nanoparticles on cells. METHODS: Cell viability was examined by MTT assay after A549 cells were exposed to 20- and 50 nm silica nanoparticles for 24 h. Radical anion (O2 -·), hydroxyl radical (·OH), hydrogen peroxide (H 2O2), nitric oxide (NO·), reactive oxygen species (ROS), malondialdehyde (MDA) contents and ATPase activity were determined after cells were treated with SiO2 nanoparticles 25, 50 and 100 mg·L-1 for 24 h. Cell apoptosis and necrosis were assessed under silica nanoparticle-exposed conditions. RESULTS: After exposure to silica nanoparticles for 24 h, the median lethal dose (LD50) was 30 ± 4 and (120 ± 14) mg·L-1 for 20- and 50 nm silica, respectively. Compared with normal control group, the content of intracellular O2 -·, ·OH, H2O2, NO·, ROS and MDA significantly increased (P < 0.05), while ATPase activity significantly decreased (P < 0.05). There was a significant reverse-correlation between cell viability and ROS or MDA content (R2 = 0.954 and R2 = 0.937). Hoechst33342/PI nucleus staining also displayed that silica nanoparticles could induce cell apoptosis and necrosis. CONCLUSION: SiO2 nanoparticles can cause cytotoxicity in A549 cells. The mechanism is possibly the overproduction of free radicals and an elevated level of oxidative stress, resulting in lipid peroxidation, cellular membrane damage, cell function disorder, cell apoptosis and necrosis.


Xu M.,Shanghai Key Laboratory of New Drug Design | Xu M.,East China University of Science and Technology | Zhu J.,Shanghai Key Laboratory of New Drug Design | Diao Y.,Shanghai Key Laboratory of New Drug Design | And 12 more authors.
Journal of Medicinal Chemistry | Year: 2013

Taking the emergence of drug resistance and lack of effective antimalarial vaccines into consideration, it is of significant importance to develop novel antimalarial agents for the treatment of malaria. Herein, we elucidated the discovery and structure-activity relationships of a series of dihydrothiophenone derivatives as novel specific inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). The most promising compound, 50, selectively inhibited PfDHODH (IC50 = 6 nM, with >14 000-fold species-selectivity over hDHODH) and parasite growth in vitro (IC50 = 15 and 18 nM against 3D7 and Dd2 cells, respectively). Moreover, an oral bioavailability of 40% for compound 50 was determined from in vivo pharmacokinetic studies. These results further indicate that PfDHODH is an effective target for antimalarial chemotherapy, and the novel scaffolds reported in this work might lead to the discovery of new antimalarial agents. © 2013 American Chemical Society.

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