Wen Tan

Name:

Organization: South China University of Technology

Department: School of Bioscience and Bioengineering

Title:

Chemicals
References

In vivo metabolism study of (R)-bambuterol in humans using ultra high performance liquid chromatography with tandem mass spectrometry

Co-reporter:Ting Zhou;Dan Zeng;Ting Zhao;Yang Yang;Shan Liu;Jie Wu;Ling Xu

Journal of Separation Science 2016 Volume 39( Issue 15) pp:2896-2906

Publication Date(Web):

DOI:10.1002/jssc.201600424

(R)-Bambuterol, a selective β2-adrenoceptor agonist, has been approved as a new drug for the treatment of asthma and chronic obstructive pulmonary disease by the China Food and Drug Administration and is currently under phase I clinical trials. In this study, a combined method based on ultra high performance liquid chromatography with triple quadrupole mass spectrometry and ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry was employed for the identification of the major metabolites of (R)-bambuterol in human plasma and urine after an oral dose of 10 mg. The metabolites were separated by gradient elution program and different sample preparation methods were compared. Totally, 12 metabolites of (R)-bambuterol were identified, including four metabolites in plasma and all 12 metabolites in urine. Among these, four metabolites are reported for the first time. The possible metabolic pathways of (R)-bambuterol were subsequently proposed. The results indicated that (R)-bambuterol was metabolized via hydrolysis, demethylation, oxygenation, glucuronidation, and sulfation pathways in vivo. This study revealed that this combined method was accurate and sensitive to identify the possible metabolites and to better understand the metabolism of (R)-bambuterol in vivo.

Resolution of Rac-Bambuterol via Diastereoisomeric Salt Formation with o-Chloromandelic Acid and Differences in the Enantiomers' Pharmacodynamical Effects in Guinea Pigs and Beagles

Co-reporter:Jie Wu;Fei Liu;Shanping Wang;Hongjun Wang;Qing Liu;Xinghan Song;Junxiao Li;Ling Xu

Chirality 2016 Volume 28( Issue 4) pp:306-312

Publication Date(Web):

DOI:10.1002/chir.22573

Abstract

In this study an enantioseparation method for rac-bambuterol (5-(2-(tert-butylamino)-1-hydroxyethyl)-1,3-phenylene bis(dimethylcarbamate)) via diastereoisomeric salt formation with o-chloromandelic acid was developed. The enantiomeric excess (ee) values and chemical purities of the desired products were confirmed by high-performance liquid chromatography (HPLC) using chiral stationary phase and reverse-phase HPLC analyses, respectively. The ee values and the chemical purities both exceeded 99%. Animal experiments showed that (R)-bambuterol was a potent inhibitor for histamine-induced asthma reactions. (S)-bambuterol was ineffective in relaxing the airways. Both enantiomers increased heart rates in beagles. Therefore, replacing rac-bambuterol with (R)-bambuterol could be beneficial for asthma patients. Chirality 28:306–312, 2016. © 2016 Wiley Periodicals, Inc.

The mechanisms of flavonoids inhibiting conformational transition of amyloid-β42 monomer: a comparative molecular dynamics simulation study

Co-reporter:Ling Wang, Ranran Zeng, Xiaoqian Pang, Qiong Gu and Wen Tan

RSC Advances 2015 vol. 5(Issue 81) pp:66391-66402

Publication Date(Web):28 Jul 2015

DOI:10.1039/C5RA12328C

Flavonoids can bind Aβ42 to inhibit the aggregation of Aβ42 monomer. However, the inhibitory mechanism remains unknown. Herein, comparable molecular dynamics simulations for a total of 710 ns were performed to study its mechanism. The in silico experiments revealed that flavonoids halt the conformational transition of Aβ42 monomer by inhibiting β-sheet formation; the flavonoids push the residues D23 and K28 of Aβ42 to be exposed to solvated water, destroy the salt bridge between D23 and K28, induce the conformational distribution of Aβ42 into local minimization energy conformational state, and generate U-shaped Aβ42 configurations, which have more stable helixes and fewer unstable random coils. Moreover, simulation results from the free energy landscape and binding free energy analyses suggest that biflavonoids are superior to monoflavonoids in inhibiting conformational transition of Aβ42 monomer. These findings agree with the experimental data and may help in the design of new agents that will inhibit the conformational transition of Aβ42 so as to treat Alzheimer's disease.

Study on the determination and chiral inversion of R-salbutamol in human plasma and urine by liquid chromatography–tandem mass spectrometry

Co-reporter:Ting Zhou, Jing Zeng, Shan Liu, Ting Zhao, Jie Wu, Wenshi Lai, Mingzhi He, Beining Xu, Shanshan Qu, Ling Xu, Wen Tan

Journal of Chromatography B 2015 Volume 1002() pp:218-227

Publication Date(Web):1 October 2015

DOI:10.1016/j.jchromb.2015.08.020

•Chiral analysis of salbutamol enantiomers in human plasma and urine.•The chiral inversion of R-salbutamol was fully investigated.•A fitted model for chiral inversion ratio of R-salbutamol was established.•The chiral inversion of R-salbutamol resulted from the gastric acid environment.•Application to a clinical pharmacokinetics study of R-salbutamol.The chiral inversion has been a concerned issue during the research and development of a chiral drug. In this study, a sensitive chiral liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for determination of salbutamol enantiomers in human plasma and urine. The chiral inversion mechanism of R-salbutamol was fully investigated for the first time by studying the effects of physicochemical factors, including pH, temperature and time. A fitted model to predict the chiral inversion ratio of R-salbutamol was proposed using a Box–Behnken design. All the samples were separated on an Astec Chirobiotic T column and detected by a tandem mass spectrometer in multiple reaction monitoring mode. Lower limit of quantification of 0.100 ng/mL was achieved under the optimized conditions. The method was fully validated and successfully applied to the clinical pharmacokinetic study of R-salbutamol in healthy volunteers. Chiral inversion of R-salbutamol to S-salbutamol has been detected in urine samples. The results indicated that pH and temperature were two dominant factors that caused the chiral inversion of R-salbutamol, which should be taken into consideration during the analysis of chiral drugs. The chiral inversion of R-salbutamol determined in this study was confirmed resulted from the gastric acid in stomach rather than caused by the analysis conditions. Moreover, the calculated results of the fitted model matched very well with the enantioselective pharmacokinetic study of R-salbutamol, and the individual difference of the chiral inversion ratio of R-salbutamol was related to the individual gastric environment. On the basis of the results, this study provides important and concrete information not only for the chiral analysis but also for the metabolism research of chiral drugs.

Chiral analysis of bambuterol, its intermediate and active drug in human plasma by liquid chromatography–tandem mass spectrometry: Application to a pharmacokinetic study

Co-reporter:Ting Zhou, Shan Liu, Ting Zhao, Jing Zeng, Mingzhi He, Beining Xu, Shanshan Qu, Ling Xu, Wen Tan

Journal of Chromatography B 2015 Volume 997() pp:38-44

Publication Date(Web):1 August 2015

DOI:10.1016/j.jchromb.2015.05.024

•Chiral analysis of bambuterol, its intermediate and active drug in human plasma.•The method achieved the highest sensitivity and the fastest analysis speed.•Application to a clinical pharmacokinetics study of rac-bambuterol.•Stereoselective metabolism exists in the metabolic process of rac-bambuterol.A sensitive liquid chromatography-tandem mass spectrometry (LC–MS/MS) method has been developed for simultaneous chiral analysis of an antiasthma drug bambuterol, its key intermediate monocarbamate bambuterol and its active drug terbutaline in human plasma. All samples were extracted with ethyl acetate and separated on an Astec Chirobiotic T column under isocratic elution with a mobile phase consisting of methanol and water with the addition of 20 mm ammonium acetate and 0.005% (v/v) formic acid at 0.6 mL/min. The analytes were detected by a Xevo TQ-S tandem mass spectrometer with positive electrospray ionization in multiple reaction monitoring mode. The established method has high sensitivity with the lower limit of quantifications of 25.00 pg/mL for bambuterol enantiomers, and 50.00 pg/mL for monocarbamate bambuterol and terbutaline enantiomers, respectively. The calibration curves for bambuterol enantiomers were linear in the range of 25.00–2500 pg/mL, and for monocarbamate bambuterol and terbutaline enantiomers were linear in the range of 50.00–5000 pg/mL. The intra- and inter-day precisions were <12.4%. All the analytes were separated in 18.0 min. For the first time, the validated method was successfully applied to an enantioselective pharmacokinetic study of rac-bambuterol in 8 healthy volunteers. According to the results, this chiral LC-MS/MS assay provides a suitable and robust method for the enantioselectivity and interaction study of the prodrug bambuterol, the key intermediate monocarbamate bambuterol and its active drug terbutaline in human.

Simultaneous determination of bambuterol and its two major metabolites in human plasma by hydrophilic interaction ultra-performance liquid chromatography–tandem mass spectrometry

Co-reporter:Ting Zhou, Qing Cheng, Chengjuan Zou, Ting Zhao, Shan Liu, Marco Pistolozzi, Evina Tan, Ling Xu, Wen Tan

Journal of Chromatography B 2014 Volume 967() pp:225-234

Publication Date(Web):15 September 2014

DOI:10.1016/j.jchromb.2014.07.022

•A HILIC–UPLC–MS2 method for analysis of bambuterol and its metabolites in plasma was developed.•Application to a clinical pharmacokinetics study of bambuterol.•The effects of chromatographic conditions on the HILIC retention were investigated.•The benefits of HILIC were evaluated by comparing with C18 ligands.In this study, a rapid and sensitive hydrophilic interaction ultra-performance liquid chromatography–tandem mass spectrometry (HILIC–UPLC–MS/MS) method was developed for simultaneous determination of bambuterol and its two major metabolites monocarbamate bambuterol and terbutaline in human plasma. All samples were simply precipitated using acetonitrile and separated on a UPLC-HILIC column under gradient elution with a mobile phase consisting of acetonitrile and water with the addition of 10 mm ammonium acetate and 0.1% formic acid at 0.4 mL/min. The analytes were detected by a Xevo TQ-S tandem mass spectrometer with positive electrospray ionization in multiple reaction monitoring mode. The established method was highly sensitive with the lower limit of quantification (LLOQ) of 10.00 pg/mL for each analyte, and the intra- and inter-day precisions were <12.8%. The analytical runtime within 4.0 min per sample made this method suitable for high throughput determination. The validated method was successfully applied to a clinical pharmacokinetic study of bambuterol in eight healthy volunteers. Furthermore, the effects of the chromatographic conditions on the retention of the analytes on HILIC were investigated, and the benefits of HILIC were evaluated by comparing with a C18 column. The results indicated that liquid–liquid partition and the electrostatic interactions played an important role in the retention of the analytes on HILIC in this study. And HILIC offered particular advantages over RPLC approach in the aspects of the peak symmetry, the column efficiency, and the column pressure.

An aerosol formulation of R-salbutamol sulfate for pulmonary inhalation

Co-reporter:Xuemei Zhang, Qing Liu, Junhua Hu, Ling Xu, Wen Tan

Acta Pharmaceutica Sinica B (February 2014) Volume 4(Issue 1) pp:

Publication Date(Web):1 February 2014

DOI:10.1016/j.apsb.2013.12.010

An aerosol formulation containing 7.5 mg of R-salbutamol sulfate was developed. The aerosol was nebulized with an air-jet nebulizer, and further assessed according to the new European Medicines Agency (EMA) guidelines. A breath simulator was used for studies of delivery rate and total amount of the active ingredient at volume of 3 mL. A next generation impactor (NGI) with a cooler was used for analysis of the particle size and in vitro lung deposition rate of the active ingredient at 5 °C. The anti-asthmatic efficacy of the aerosol formulation was assessed in guinea pigs with asthma evoked by intravenous injection of histamine compared with racemic salbutamol. Our results show that this aerosol formulation of R-salbutamol sulfate met all the requirements of the new EMA guidelines for nebulizer. The efficacy of a half-dose of R-salbutamol equaled that of a normal dose of racemic salbutamol.Drug particles will deposit in different stages of NGI which simulate the lower respiratory tract structure approximately. Also alleviation of airway hyperreactivity by inhaling R-salbutamol sulfate solution was validated both in airway resistance and in dynamic compliance of lung compared with racemic salbutamol.Download full-size image

Network pharmacology-based study on the mechanism of action for herbal medicines in Alzheimer treatment

Co-reporter:Jiansong Fang, Ling Wang, Tian Wu, Cong Yang, Li Gao, Haobin Cai, Junhui Liu, Shuhuan Fang, Yunbo Chen, Wen Tan, Qi Wang

Journal of Ethnopharmacology (20 January 2017) Volume 196() pp:281-292

Publication Date(Web):20 January 2017

DOI:10.1016/j.jep.2016.11.034

Ethnopharmacological relevanceAlzheimer's disease (AD), as the most common type of dementia, has brought a heavy economic burden to healthcare system around the world. However, currently there is still lack of effective treatment for AD patients. Herbal medicines, featured as multiple herbs, ingredients and targets, have accumulated a great deal of valuable experience in treating AD although the exact molecular mechanisms are still unclear.Materials and methodsIn this investigation, we proposed a network pharmacology-based method, which combined large-scale text-mining, drug-likeness filtering, target prediction and network analysis to decipher the mechanisms of action for the most widely studied medicinal herbs in AD treatment.ResultsThe text mining of PubMed resulted in 10 herbs exhibiting significant correlations with AD. Subsequently, after drug-likeness filtering, 1016 compounds were remaining for 10 herbs, followed by structure clustering to sum up chemical scaffolds of herb ingredients. Based on target prediction results performed by our in-house protocol named AlzhCPI, compound-target (C-T) and target-pathway (T-P) networks were constructed to decipher the mechanism of action for anti-AD herbs.ConclusionsOverall, this approach provided a novel strategy to explore the mechanisms of herbal medicine from a holistic perspective.Download high-res image (157KB)Download full-size image

Design, synthesis, biological evaluation, and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors

Co-reporter:Ling Wang, Yu Wang, Yiguang Tian, Jinling Shang, Xiaoou Sun, Hongzhuan Chen, Hao Wang, Wen Tan

Bioorganic & Medicinal Chemistry (1 January 2017) Volume 25(Issue 1) pp:

Publication Date(Web):1 January 2017

DOI:10.1016/j.bmc.2016.11.002

•A series of novel chalcone-rivastigmine hybrids have been designed and synthesized.•Biochemical assessment of cholinesterase enzyme has been carried out.•Some of the designed compounds showed promising anticholinesterase activity and low toxicity.•Compound 3 blocked the formation of reactive oxygen species (ROS) in SH-SY5Y cells.•Molecular docking and molecular dynamics simulations studies have been done.A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC50 to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer’s disease (AD) treatment.

Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy

Co-reporter:Hongguang Sun, Xun Zhu, Patrick Y Lu, Roberto R Rosato, ... Youli Zu

Molecular Therapy - Nucleic Acids Volume 3() pp:

Publication Date(Web):1 January 2014

DOI:10.1038/mtna.2014.32

Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed “chemical antibodies.” In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy.