Qingwang Liu

Hefei Institutes of Physical Science

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Qingsong Liu

Chengdu Academy of Agriculture and Forestry Sciences

Jing Liu

Suizhou Central Hospital

Beilei Wang

Chongqing Medical and Pharmaceutical College

Aoli Wang

Hefei Institutes of Physical Science

Fengming Zou

Hefei Institutes of Physical Science

Ziping Qi

Chinese Academy of Sciences

Zhenquan Hu

Hefei Institutes of Physical Science

Li Wang

Guizhou University

Tao Ren

Shanghai Sixth People's Hospital

Cheng Chen

University of Science and Technology of China

Cooperative Institutions

Chinese Academy of Sciences

Hefei Institutes of Physical Science

University of Science and Technology of China

Anhui Medical University

China Pharmaceutical University

High Magnetic Field Laboratory

Zhejiang University

Shanghai Jiao Tong University

University of Chinese Academy of Sciences

Sun Yat-sen University

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Low dose of emetine as potential anti-SARS-CoV-2 virus therapy: preclinical in vitro inhibition and in vivo pharmacokinetic evidences

Molecular Biomedicine (2020)

Aoli Wang Yong Sun Qingwang Liu Hong Wu Juan Liu

The global pandemic of COVID-19 has attracted extensive drug searching interets for the new coronavirus SARS-CoV-2. Although currently several of clinically used "old" drugs have been repurposed to this new disease for the urgent clinical investigation, there is still great demand for more effective therapies for the anti-infections. Here we report the discovery that an "old" drug Emetine could potently inhibit SARS-CoV-2 virus replication and displayed virus entry blocking effect in Vero cells at low dose. In addition, Emetine could significantly reduce the lipopolysaccharide (LPS) induced interleukin-6 (IL-6) protein level and moderately reduce the tumor necrosis factor (TNF-α) protein level in the M1 polarized THP-1 macrophages. In vivo animal pharmacokinetics (PK) study revealed that Emetine was enriched in the lung tissue and had a long retention time (over 12 h). With 1 mg/kg single oral dose, the effective concentration of Emetine in lung was up to 1.8 μM (mice) and 1.6 μM (rats) at 12 h, which is over 200-fold higher than the EC50 of the drug. The potent in vitro antiviral replication efficacy and the high enrichment in target tissue, combining with the well documented safety profiles in human indicate that low dose of Emetine might be a potentially effective anti-SARS-CoV-2 infection therapy.

Emetine

Vero cell

10.1186/s43556-020-00018-9

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Citations (25)

Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML)

European Journal of Pharmacology (2021)

Tingting Lu Jiangyan Cao Fengming Zou Xixiang Li Aoli Wang

Chronic myelogenous leukemia

ABL

K562 cells

STAT5

Imatinib Mesylate

10.1016/j.ejphar.2021.173944

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Citations (7)

Discovery of 6′-chloro-N-methyl-5’-(phenylsulfonamido)-[3,3′-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium

European Journal of Medicinal Chemistry (2019)

Xiaofei Liang Zongru Jiang Zhenghui Huang Feng Li Cheng Chen

IC50

10.1016/j.ejmech.2019.112012

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Citations (16)

Limiting Partial Molar Volumes of Glycine, l-Alanine, and l-Serine in Ethylene Glycol + Water Mixtures at 298.15 K.

Journal of Chemical & Engineering Data (2001)

Qingwang Liu Xingen Hu Ruisen Lin Wenqiang Sang Shuqin Li

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionORIGINAL ARTICLEThis notice is a correctionLimiting Partial Molar Volumes of Glycine, l-Alanine, and l-Serine in Ethylene Glycol + Water Mixtures at 298.15 K.Qingwang Liu, Xingen Hu, Ruisen Lin, Wenqiang Sang, and Shuqin LiCite this: J. Chem. Eng. Data 2001, 46, 3, 782Publication Date (Web):May 10, 2001Publication History Published online10 May 2001Published inissue 1 May 2001https://pubs.acs.org/doi/10.1021/je010499shttps://doi.org/10.1021/je010499scorrectionACS PublicationsCopyright © 2001 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views247Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (8 KB) Get e-Alertsclose Get e-Alerts

Alanine

Limiting

10.1021/je010499s

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PEG-Bottlebrush Stabilizer-Based Worm-like Nanocrystal Micelles with Long-Circulating and Controlled Release for Delivery of a BCR-ABL Inhibitor against Chronic Myeloid Leukemia (CML)

Pharmaceutics (2022)

Huamin Liang Fengming Zou Liyi Fu Qingwang Liu Beilei Wang

Drug nanocrystals, one of most common drug delivery systems, enable the delivery of poorly water-soluble drugs with high drug loading and enhanced dissolution. The rapid clearance and uncontrolled drug release of drug nanocrystals limit their delivery efficiency and clinical application. Herein, an amphiphilic co-polymer, poly oligo(ethylene glycol) methacrylate-b-poly(styrene–co-4-formylphenyl methacrylate) (POEGMA-b-P (St-co-FPMA), PPP), characterized by a hydrophilic part with bottlebrush-like oligo(ethylene glycol) methacrylate (OEGMA) side chains, was synthesized as stabilizers to fabricate a high-drug-loading nanocrystal micelle (053-PPP NC micelle) using the chronic myeloid leukemia (CML) drug candidate N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053 or 053) as a model drug. The 053-PPP NC micelle was characterized and subjected to in vitro and in vivo studies. It featured a worm-like shape of small size, high drug loading (~50%), high colloidal stability, and controlled release in vitro. The presence of the 053-PPP NC micelle resulted in a long-circulation property and a much higher AUC. The 053-PPP NC micelle induced higher accumulation in the tumor tissues under multiple continuous administration. For in vivo efficacy, the 053-PPP NC micelle with a longer dosing interval (96 h), beneficial for improving patient adherence, demonstrated superiority to the 053-F127 NC. The proposed stabilizer PPP and the 053-PPP NC micelle with high drug loading enables drug delivery with long circulation and controlled release of drugs. It is also promising for the development of more efficient nanocrystal-based intravenous injection formulations for poorly water-soluble drugs. It might also offer new possibilities for potential clinical application of the CML candidate drug 053.

10.3390/pharmaceutics14081662

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Citations (4)

Cytochrome P450 3A4-Mediated Bioactivation and Its Role in Nomilin-Induced Hepatotoxicity

Chemical Research in Toxicology (2020)

Lei Zhang Qingwang Liu Yajuan Pan Xianfang Qi Yuanlong Li

Nomilin is a furan-containing triterpenoid isolated from the medicinal plants of citrus. The aim of this study was to investigate the in vitro and in vivo bioactivation of nomilin and the role in nomilin-induced hepatotoxicity. Microsomal incubations of nomilin supplemented with NADPH and GSH or NAL resulted in the detection of six conjugates (M1–M6). The structures of the metabolites were characterized based on LC-HRMS and NMR. Nomilin was bioactivated to a reactive cis-butene-dial (BDA) intermediate dependent on NADPH, and this intermediate suffered from the reaction with the nucleophiles (GSH and NAL) to form stable adducts. M1–M4 were identified as pyrrole derivatives, and M5 and M6 were pyrrolinone derivatives. M1 was further chemically synthesized and characterized by 13C NMR spectroscopy. M1 was the major metabolite detected in mice bile. Pretreatment with ketoconazole significantly reduced the formation of M1 in mice bile, while pretreatment with rifampicin significantly increased the formation of M1. Chemical inhibition together with recombinant human CYP450 phenotyping demonstrated that CYP3A4 was the major enzyme contributing to the bioactivation of nomilin. Toxicity study suggested that nomilin displayed dose-dependent liver injury in mice, while tetrahydro-nomilin was found to be nonhepatotoxic. Pretreatment with ketoconazole prevented mice from nomilin-induced liver injury. The liver injury induced by nomilin was deteriorated when the mice were pretreated with rifampicin. These findings provide evidence that CYP3A4-mediated bioactivation was indispensable in nomilin-induced hepatotoxicity.

10.1021/acs.chemrestox.0c00228

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Citations (6)

Identification and characterization of the metabolites of moscatilin in mouse, rat, dog, monkey and human hepatocytes by LC–Orbitrap–MS/MS combined with diagnostic fragment ions and accurate mass measurements

Biomedical Chromatography (2022)

Aizhen Hu Qingwang Liu Jing Ouyang

Moscatilin, a bibenzyl derivative from the stem of Dendrobium loddigesii, has been shown to have anticancer activity. The aim of this study was to identify and characterize the possible in vitro metabolites of moscatilin generated from hepatocytes. The metabolites generated in the hepatocytes of mouse, rat, dog, monkey and human were identified and characterized employing ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap tandem mass spectrometry (LC-Orbitrap-MS/MS) based on diagnostic fragment ions and accurate mass measurements. A total of 18 metabolites were identified, among which seven were phase I and 11 were phase II metabolites. The plausible structures of the metabolites and the probable biotransformation pathways were proposed based on the diagnostic fragment ions, chemical formula and mass fragmentation pattern, as well as the accurate masses. The majority of phase I metabolites were generated by demethylation and hydroxylation, while phase II metabolites were mainly generated by glucuronidation, glutathione conjugation and sulfation. Our study first expounded the metabolites of moscatilin in mouse, rat, dog, monkey and human hepatocytes and provided a foundation for a further pharmacokinetic and toxicity study. More importantly, LC-Orbitrap-MS/MS combined with diagnostic fragment ions and accurate mass measurements has been proved to be an effective method for the rapid identification of bibenzyl derivatives and their metabolites.

Orbitrap

Fragment (logic)

Identification

Characterization

10.1002/bmc.5573

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Citations (2)

Identification and analysis of gastrodin and its five metabolites using ultra fast liquid chromatography electrospray ionization tandem mass spectrometry to investigate influence of multiple-dose and food

Journal of Chromatography A (2014)

Yuanwei Jia Jie Shen Xin Li Haitang Xie Junsong Wang

Gastrodin

10.1016/j.chroma.2014.06.080

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Citations (17)

Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mutants in FLT3-ITD Positive AML

Journal of Medicinal Chemistry (2017)

Aoli Wang Xixiang Li Cheng Chen Wu Hong Ziping Qi

FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of our previous study that ibrutinib (9) exhibited selective and moderate inhibitory activity against FLT3-ITD positive AML cells, through a structure-guided drug design approach, we have discovered a new type II FLT3 kinase inhibitor, compound 14 (CHMFL-FLT3-213), which exhibited highly potent inhibitory effects against FLT3-ITD mutant and associated oncogenic mutations (including FLT3-D835Y/H/V, FLT3-ITD-D835Y/I/N/A/G/Del, and FLT3-ITD-F691L). In the cellular context 14 strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting cell cycle into G0/G1 phase. In the in vivo studies 14 demonstrated an acceptable bioavailability (F = 19%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (15 mg kg–1 day–1, TGI = 97%) without exhibiting obvious toxicity. Compound 14 might be a potential drug candidate for FLT3-ITD positive AML.

10.1021/acs.jmedchem.7b00840

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Citations (36)

Analysis and pharmacokinetics studies of gastrodin and p-hydroxybenzyl alcohol in dogs using ultra fast liquid chromatography–tandem mass spectrometry method

Journal of Pharmaceutical and Biomedical Analysis (2014)

Yuanwei Jia Xin Li Haitang Xie Jie Shen Jun Luo

Gastrodin

10.1016/j.jpba.2014.07.004

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Citations (25)