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Zhengtao Wang - One of the best experts on this subject based on the ideXlab platform.
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Acetylcholinesterase and Butyrylcholinesterase Inhibitory Activities of -Carboline and Quinoline Alkaloids Derivatives from the Plants of Genus Peganum
2020Co-Authors: Ting Zhao, Xuemei Cheng, Changhong Wang, Zhengtao Wang, Kemin Ding, Lei Zhang, Hamid A HadiAbstract:It was reported that the main chemical constituents in plants of genus Peganum were a serial of -carboline and quinoline alkaloids. These alkaloids were quantitatively assessed for selective inhibitory activities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by in vitro Ellman method. The results indicated that harmane was the most potent selective AChE inhibitor with an IC 50 of 7.11 ± 2.00 M and AChE selectivity index (SI, IC 50 of BChE/IC 50 of AChE) of 10.82. Vasicine was the most potent BChE inhibitor with feature of dual AChE/BChE inhibitory activity, with an IC 50 versus AChE/BChE of 13.68 ± 1.25/2.60 ± 1.47 M and AChE SI of 0.19. By analyzing and comparing the IC 50 and SI of those chemicals, it was indicated that the -carboline alkaloids displayed more potent AChE inhibition but less BChE inhibition than quinoline alkaloids. The substituent at the C7 position of the -carboline alkaloids and C3 and C9 positions of quinoline alkaloids played a critical role in AChE or BChE inhibition. The potent inhibition suggested that those alkaloids may be used as candidates for treatment of Alzheimer's disease. The analysis of the quantitative structure-activity relationship of those compounds investigated might provide guidance for the design and synthesis of AChE and BChE inhibitors
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antitussive expectorant and bronchodilating effects of quinazoline alkaloids Vasicine deoxyVasicine and vasicinone from aerial parts of peganum harmala l
Phytomedicine, 2015Co-Authors: Yongli Wang, Xuemei Cheng, Bo Jiang, Zhengtao Wang, Dandan He, Shuping Li, Changhong WangAbstract:Abstract Background The aerial parts of Peganum harmala L. (APP) is a well-known and effective herbal medicine in China, and has been commonly used for treating various ailments, including cough and asthma. Objectives To evaluate the antitussive, expectorant, and bronchodilating effects of the quinazoline alkaloids (±)-Vasicine (VAS), deoxyVasicine (DVAS) (both isolated from the alkaloid fraction of APP) and (±)-vasicinone (VAO) (synthesized from VAS). Methods The three quinazoline alkaloids were tested as antitussive on cough models in mice and guinea pigs. VAO was synthesized from VAS via the oxidation of hydrogen peroxide. VAS, VAO, and DVAS were orally administered at dosages of 5, 15, and 45 mg/kg. Cough in these models was induced by ammonia, capsaicin, and citric acid. Phenol red secretion experiments in mice were performed to evaluate the expectorant activity of the alkaloids. Bronchodilating effects were evaluated by using a bronchoconstrictive induced by acetylcholine chloride and histamine in guinea pigs. Results In antitussive tests, VAS, VAO, and DVAS significantly inhibited coughing frequency and prolonged the cough latency period in animals. At the highest doses tested (45 mg/kg), they showed antitussive activities similar to codeine phosphate (30 mg/kg) in mice and guinea pigs. Expectorant evaluation showed that VAS, VAO, and DVAS could significantly increase phenol red secretion in mice by 0.54-, 0.79- and 0.97-fold, by 0.60-, 0.99-, and 1.06-fold, and by 0.46-, 0.73-, and 0.96-fold, respectively, at dosages of 5, 15, and 45 mg/kg compared with the control (0.5% CMC-Na, 20 ml/kg). Ammonium chloride at 1500 mg/kg increased phenol red secretion in mice by 0.97-fold compared with the control. Bronchodilation tests showed that VAS, VAO, and DVAS prolonged the pre-convulsive time for 28.59%, 57.21%, and 29.66%, respectively, at a dose of 45 mg/kg in guinea pigs, whereas aminophylline prolonged the pre-convulsive time by 46.98% compared with pretreatment. Conclusions Quinazoline alkaloids VAS, VAO, and DVAS have significant antitussive, expectorant, and bronchodilating activities. VAS, VAO, and DVAS are the active ingredients in APP, which can be used to treat respiratory disease.
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in vitro and in vivo metabolism and inhibitory activities of Vasicine a potent acetylcholinesterase and butyrylcholinesterase inhibitor
PLOS ONE, 2015Co-Authors: Wei Liu, Xiaoyuan Shi, Yadi Yang, Xuemei Cheng, Qing Liu, Han Han, Baohua Yang, Yongli Wang, Bo Jiang, Zhengtao WangAbstract:Vasicine (VAS), a potential natural cholinesterase inhibitor, exhibited promising anticholinesterase activity in preclinical models and has been in development for treatment of Alzheimer’s disease. This study systematically investigated the in vitro and in vivo metabolism of VAS in rat using ultra performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 72 metabolites were found based on a detailed analysis of their 1H- NMR and 13C NMR data. Six key metabolites were isolated from rat urine and elucidated as vasicinone, vasicinol, vasicinolone, 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, 9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, and 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-β-D-glucuronide. The metabolic pathway of VAS in vivo and in vitro mainly involved monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of VAS were the 3-hydroxyl group and the C-9 site. All 72 metabolites were found in the urine sample, and 15, 25, 45, 18, and 11 metabolites were identified from rat feces, plasma, bile, rat liver microsomes, and rat primary hepatocyte incubations, respectively. Results indicated that renal clearance was the major excretion pathway of VAS. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of VAS and its main metabolites were also evaluated. The results indicated that although most metabolites maintained potential inhibitory activity against AChE and BChE, but weaker than that of VAS. VAS undergoes metabolic inactivation process in vivo in respect to cholinesterase inhibitory activity.
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chemical fingerprint and simultaneous determination of alkaloids and flavonoids in aerial parts of genus peganum indigenous to china based on hplc uv application of analysis on secondary metabolites accumulation
Biomedical Chromatography, 2014Co-Authors: Xuemei Cheng, Zhengtao Wang, Lei Zhang, Min Xuan, Xin Zhao, Meng Shan, Yan Li, Liang Teng, Changhong WangAbstract:The aerial parts of genus Peganum are officially used in traditional Chinese medicine. The paper aims to establish a high-performance liquid chromatography (HPLC) method for fingerprint analysis and simultaneous determination of three alkaloids and two flavonoids in aerial parts of genus Peganum, and to analyze accumulative difference of secondary metabolites in inter-species, individuals of plants, inter-/intra-population and from different growing seasons. HPLC analysis was performed on a C18 column with gradient elution using 0.1% trifloroacetic acid and acetonitrile as mobile phase and detected at 265 nm, by conventional methodology validation. For fingerprint analysis, the RSDs of relative retention time and relative peak area of the characteristic peaks were within 0.07–0.78 and 0.94–9.09%, respectively. For simultaneous determination of Vasicine, harmaline, harmine, deacetylpeganetin and peganetin, all calibration curves showed good linearity (r > 0.9990) within the test range. The relative standard deviations of precision, repeatability and stability test did not exceed 2.37, 2.68 and 2.67%, respectively. The average recoveries for the five analytes were between 96.47 and 101.20%. HPLC fingerprints play a minor role in authenticating and differentiating the herbs of different species of genus Peganum. However, the secondary metabolites levels of alkaloids and flavonoids in aerial parts of genus Peganum rely on species-, habitat-, and growth season-dependent accumulation. Copyright © 2014 John Wiley & Sons, Ltd.
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acetylcholinesterase and butyrylcholinesterase inhibitory activities of β carboline and quinoline alkaloids derivatives from the plants of genus peganum
Journal of Chemistry, 2013Co-Authors: Ting Zhao, Xuemei Cheng, Changhong Wang, Kemin Ding, Lei Zhang, Zhengtao WangAbstract:It was reported that the main chemical constituents in plants of genus Peganum were a serial of β-carboline and quinoline alkaloids. These alkaloids were quantitatively assessed for selective inhibitory activities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by in vitro Ellman method. The results indicated that harmane was the most potent selective AChE inhibitor with an IC50 of 7.11 ± 2.00 μM and AChE selectivity index (SI, IC50 of BChE/IC50 of AChE) of 10.82. Vasicine was the most potent BChE inhibitor with feature of dual AChE/BChE inhibitory activity, with an IC50 versus AChE/BChE of 13.68 ± 1.25/2.60 ± 1.47 μM and AChE SI of 0.19. By analyzing and comparing the IC50 and SI of those chemicals, it was indicated that the β-carboline alkaloids displayed more potent AChE inhibition but less BChE inhibition than quinoline alkaloids. The substituent at the C7 position of the β-carboline alkaloids and C3 and C9 positions of quinoline alkaloids played a critical role in AChE or BChE inhibition. The potent inhibition suggested that those alkaloids may be used as candidates for treatment of Alzheimer’s disease. The analysis of the quantitative structure-activity relationship of those compounds investigated might provide guidance for the design and synthesis of AChE and BChE inhibitors.
Changhong Wang - One of the best experts on this subject based on the ideXlab platform.
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Acetylcholinesterase and Butyrylcholinesterase Inhibitory Activities of -Carboline and Quinoline Alkaloids Derivatives from the Plants of Genus Peganum
2020Co-Authors: Ting Zhao, Xuemei Cheng, Changhong Wang, Zhengtao Wang, Kemin Ding, Lei Zhang, Hamid A HadiAbstract:It was reported that the main chemical constituents in plants of genus Peganum were a serial of -carboline and quinoline alkaloids. These alkaloids were quantitatively assessed for selective inhibitory activities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by in vitro Ellman method. The results indicated that harmane was the most potent selective AChE inhibitor with an IC 50 of 7.11 ± 2.00 M and AChE selectivity index (SI, IC 50 of BChE/IC 50 of AChE) of 10.82. Vasicine was the most potent BChE inhibitor with feature of dual AChE/BChE inhibitory activity, with an IC 50 versus AChE/BChE of 13.68 ± 1.25/2.60 ± 1.47 M and AChE SI of 0.19. By analyzing and comparing the IC 50 and SI of those chemicals, it was indicated that the -carboline alkaloids displayed more potent AChE inhibition but less BChE inhibition than quinoline alkaloids. The substituent at the C7 position of the -carboline alkaloids and C3 and C9 positions of quinoline alkaloids played a critical role in AChE or BChE inhibition. The potent inhibition suggested that those alkaloids may be used as candidates for treatment of Alzheimer's disease. The analysis of the quantitative structure-activity relationship of those compounds investigated might provide guidance for the design and synthesis of AChE and BChE inhibitors
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antitussive expectorant and bronchodilating effects of quinazoline alkaloids Vasicine deoxyVasicine and vasicinone from aerial parts of peganum harmala l
Phytomedicine, 2015Co-Authors: Yongli Wang, Xuemei Cheng, Bo Jiang, Zhengtao Wang, Dandan He, Shuping Li, Changhong WangAbstract:Abstract Background The aerial parts of Peganum harmala L. (APP) is a well-known and effective herbal medicine in China, and has been commonly used for treating various ailments, including cough and asthma. Objectives To evaluate the antitussive, expectorant, and bronchodilating effects of the quinazoline alkaloids (±)-Vasicine (VAS), deoxyVasicine (DVAS) (both isolated from the alkaloid fraction of APP) and (±)-vasicinone (VAO) (synthesized from VAS). Methods The three quinazoline alkaloids were tested as antitussive on cough models in mice and guinea pigs. VAO was synthesized from VAS via the oxidation of hydrogen peroxide. VAS, VAO, and DVAS were orally administered at dosages of 5, 15, and 45 mg/kg. Cough in these models was induced by ammonia, capsaicin, and citric acid. Phenol red secretion experiments in mice were performed to evaluate the expectorant activity of the alkaloids. Bronchodilating effects were evaluated by using a bronchoconstrictive induced by acetylcholine chloride and histamine in guinea pigs. Results In antitussive tests, VAS, VAO, and DVAS significantly inhibited coughing frequency and prolonged the cough latency period in animals. At the highest doses tested (45 mg/kg), they showed antitussive activities similar to codeine phosphate (30 mg/kg) in mice and guinea pigs. Expectorant evaluation showed that VAS, VAO, and DVAS could significantly increase phenol red secretion in mice by 0.54-, 0.79- and 0.97-fold, by 0.60-, 0.99-, and 1.06-fold, and by 0.46-, 0.73-, and 0.96-fold, respectively, at dosages of 5, 15, and 45 mg/kg compared with the control (0.5% CMC-Na, 20 ml/kg). Ammonium chloride at 1500 mg/kg increased phenol red secretion in mice by 0.97-fold compared with the control. Bronchodilation tests showed that VAS, VAO, and DVAS prolonged the pre-convulsive time for 28.59%, 57.21%, and 29.66%, respectively, at a dose of 45 mg/kg in guinea pigs, whereas aminophylline prolonged the pre-convulsive time by 46.98% compared with pretreatment. Conclusions Quinazoline alkaloids VAS, VAO, and DVAS have significant antitussive, expectorant, and bronchodilating activities. VAS, VAO, and DVAS are the active ingredients in APP, which can be used to treat respiratory disease.
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chemical fingerprint and simultaneous determination of alkaloids and flavonoids in aerial parts of genus peganum indigenous to china based on hplc uv application of analysis on secondary metabolites accumulation
Biomedical Chromatography, 2014Co-Authors: Xuemei Cheng, Zhengtao Wang, Lei Zhang, Min Xuan, Xin Zhao, Meng Shan, Yan Li, Liang Teng, Changhong WangAbstract:The aerial parts of genus Peganum are officially used in traditional Chinese medicine. The paper aims to establish a high-performance liquid chromatography (HPLC) method for fingerprint analysis and simultaneous determination of three alkaloids and two flavonoids in aerial parts of genus Peganum, and to analyze accumulative difference of secondary metabolites in inter-species, individuals of plants, inter-/intra-population and from different growing seasons. HPLC analysis was performed on a C18 column with gradient elution using 0.1% trifloroacetic acid and acetonitrile as mobile phase and detected at 265 nm, by conventional methodology validation. For fingerprint analysis, the RSDs of relative retention time and relative peak area of the characteristic peaks were within 0.07–0.78 and 0.94–9.09%, respectively. For simultaneous determination of Vasicine, harmaline, harmine, deacetylpeganetin and peganetin, all calibration curves showed good linearity (r > 0.9990) within the test range. The relative standard deviations of precision, repeatability and stability test did not exceed 2.37, 2.68 and 2.67%, respectively. The average recoveries for the five analytes were between 96.47 and 101.20%. HPLC fingerprints play a minor role in authenticating and differentiating the herbs of different species of genus Peganum. However, the secondary metabolites levels of alkaloids and flavonoids in aerial parts of genus Peganum rely on species-, habitat-, and growth season-dependent accumulation. Copyright © 2014 John Wiley & Sons, Ltd.
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acetylcholinesterase and butyrylcholinesterase inhibitory activities of β carboline and quinoline alkaloids derivatives from the plants of genus peganum
Journal of Chemistry, 2013Co-Authors: Ting Zhao, Xuemei Cheng, Changhong Wang, Kemin Ding, Lei Zhang, Zhengtao WangAbstract:It was reported that the main chemical constituents in plants of genus Peganum were a serial of β-carboline and quinoline alkaloids. These alkaloids were quantitatively assessed for selective inhibitory activities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by in vitro Ellman method. The results indicated that harmane was the most potent selective AChE inhibitor with an IC50 of 7.11 ± 2.00 μM and AChE selectivity index (SI, IC50 of BChE/IC50 of AChE) of 10.82. Vasicine was the most potent BChE inhibitor with feature of dual AChE/BChE inhibitory activity, with an IC50 versus AChE/BChE of 13.68 ± 1.25/2.60 ± 1.47 μM and AChE SI of 0.19. By analyzing and comparing the IC50 and SI of those chemicals, it was indicated that the β-carboline alkaloids displayed more potent AChE inhibition but less BChE inhibition than quinoline alkaloids. The substituent at the C7 position of the β-carboline alkaloids and C3 and C9 positions of quinoline alkaloids played a critical role in AChE or BChE inhibition. The potent inhibition suggested that those alkaloids may be used as candidates for treatment of Alzheimer’s disease. The analysis of the quantitative structure-activity relationship of those compounds investigated might provide guidance for the design and synthesis of AChE and BChE inhibitors.
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acetylcholinesterase inhibitive activity guided isolation of two new alkaloids from seeds of peganum nigellastrum bunge by an in vitro tlc bioautographic assay
Archives of Pharmacal Research, 2009Co-Authors: Xiyuan Zheng, Xuemei Cheng, Zijia Zhang, Guixin Chou, Changhong Wang, Zhengtao WangAbstract:Acetylcholinesterase inhibitors (AChEIs) currently form the basis of the newest drugs available for the treatment of Alzheimer’s disease. For the aim of screening effective AChEIs, the methanol extracts of the seeds of genus Peganum were found to show significant inhibitory activity of acetylcholinesterase enzyme (AChE) using an in vitro TLC-bioautographic assay. In further studies to seed of P. nigellastrum Bunge, activity-guided fractionation led to the isolation of two new alkaloids nigellastrine I (9) and nigellastrine II (10), and along with eight known alkaloids, vasicinone (1), Vasicine (2), harmine (3), deoxyvasicinone (4), deoxyVasicine (5), harmaline (6), harmol (7), harman (8), in which harmol and harman were first isolated from species P. nigellastrum Bunge. As active constituents, all compounds showed good inhibitory activities against AChE. The results of in vitro semi-quality TLC-bioautographic assay showed that harmine, harmaline and harmol displayed a similar AChE inhibitive activities comparing to galanthamine. These results indicated that these alkaloids in P. nigellastrum Bunge could be a potent class of AChEIs.
Xuemei Cheng - One of the best experts on this subject based on the ideXlab platform.
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Acetylcholinesterase and Butyrylcholinesterase Inhibitory Activities of -Carboline and Quinoline Alkaloids Derivatives from the Plants of Genus Peganum
2020Co-Authors: Ting Zhao, Xuemei Cheng, Changhong Wang, Zhengtao Wang, Kemin Ding, Lei Zhang, Hamid A HadiAbstract:It was reported that the main chemical constituents in plants of genus Peganum were a serial of -carboline and quinoline alkaloids. These alkaloids were quantitatively assessed for selective inhibitory activities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by in vitro Ellman method. The results indicated that harmane was the most potent selective AChE inhibitor with an IC 50 of 7.11 ± 2.00 M and AChE selectivity index (SI, IC 50 of BChE/IC 50 of AChE) of 10.82. Vasicine was the most potent BChE inhibitor with feature of dual AChE/BChE inhibitory activity, with an IC 50 versus AChE/BChE of 13.68 ± 1.25/2.60 ± 1.47 M and AChE SI of 0.19. By analyzing and comparing the IC 50 and SI of those chemicals, it was indicated that the -carboline alkaloids displayed more potent AChE inhibition but less BChE inhibition than quinoline alkaloids. The substituent at the C7 position of the -carboline alkaloids and C3 and C9 positions of quinoline alkaloids played a critical role in AChE or BChE inhibition. The potent inhibition suggested that those alkaloids may be used as candidates for treatment of Alzheimer's disease. The analysis of the quantitative structure-activity relationship of those compounds investigated might provide guidance for the design and synthesis of AChE and BChE inhibitors
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RESEARCH ARTICLE In Vitro and In Vivo Metabolism and Inhibitory Activities of Vasicine, a Potent
2016Co-Authors: Butyrylcholinesterase Inhibitor, Wei Liu, Xiaoyuan Shi, Yadi Yang, Xuemei Cheng, Qing Liu, Han Han, Baohua YangAbstract:Vasicine (VAS), a potential natural cholinesterase inhibitor, exhibited promising anticholin-esterase activity in preclinical models and has been in development for treatment of Alzhei-mer’s disease. This study systematically investigated the in vitro and in vivo metabolism of VAS in rat using ultra performance liquid chromatography combined with electrospray ioni-zation quadrupole time-of-flight mass spectrometry. A total of 72 metabolites were found based on a detailed analysis of their 1H- NMR and 13C NMR data. Six key metabolites were isolated from rat urine and elucidated as vasicinone, vasicinol, vasicinolone, 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, 9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, and 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-β-D-glucuronide. The metabolic pathway of VAS in vivo and in vitro mainly involved monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of VAS were the 3-hydroxyl group and the C-9 site. All 72 metabolites were found in the urine sample, and 15, 25, 45, 18, and 11 metabolites were identified from rat feces, plasma, bile, rat liver micro
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antitussive expectorant and bronchodilating effects of quinazoline alkaloids Vasicine deoxyVasicine and vasicinone from aerial parts of peganum harmala l
Phytomedicine, 2015Co-Authors: Yongli Wang, Xuemei Cheng, Bo Jiang, Zhengtao Wang, Dandan He, Shuping Li, Changhong WangAbstract:Abstract Background The aerial parts of Peganum harmala L. (APP) is a well-known and effective herbal medicine in China, and has been commonly used for treating various ailments, including cough and asthma. Objectives To evaluate the antitussive, expectorant, and bronchodilating effects of the quinazoline alkaloids (±)-Vasicine (VAS), deoxyVasicine (DVAS) (both isolated from the alkaloid fraction of APP) and (±)-vasicinone (VAO) (synthesized from VAS). Methods The three quinazoline alkaloids were tested as antitussive on cough models in mice and guinea pigs. VAO was synthesized from VAS via the oxidation of hydrogen peroxide. VAS, VAO, and DVAS were orally administered at dosages of 5, 15, and 45 mg/kg. Cough in these models was induced by ammonia, capsaicin, and citric acid. Phenol red secretion experiments in mice were performed to evaluate the expectorant activity of the alkaloids. Bronchodilating effects were evaluated by using a bronchoconstrictive induced by acetylcholine chloride and histamine in guinea pigs. Results In antitussive tests, VAS, VAO, and DVAS significantly inhibited coughing frequency and prolonged the cough latency period in animals. At the highest doses tested (45 mg/kg), they showed antitussive activities similar to codeine phosphate (30 mg/kg) in mice and guinea pigs. Expectorant evaluation showed that VAS, VAO, and DVAS could significantly increase phenol red secretion in mice by 0.54-, 0.79- and 0.97-fold, by 0.60-, 0.99-, and 1.06-fold, and by 0.46-, 0.73-, and 0.96-fold, respectively, at dosages of 5, 15, and 45 mg/kg compared with the control (0.5% CMC-Na, 20 ml/kg). Ammonium chloride at 1500 mg/kg increased phenol red secretion in mice by 0.97-fold compared with the control. Bronchodilation tests showed that VAS, VAO, and DVAS prolonged the pre-convulsive time for 28.59%, 57.21%, and 29.66%, respectively, at a dose of 45 mg/kg in guinea pigs, whereas aminophylline prolonged the pre-convulsive time by 46.98% compared with pretreatment. Conclusions Quinazoline alkaloids VAS, VAO, and DVAS have significant antitussive, expectorant, and bronchodilating activities. VAS, VAO, and DVAS are the active ingredients in APP, which can be used to treat respiratory disease.
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in vitro and in vivo metabolism and inhibitory activities of Vasicine a potent acetylcholinesterase and butyrylcholinesterase inhibitor
PLOS ONE, 2015Co-Authors: Wei Liu, Xiaoyuan Shi, Yadi Yang, Xuemei Cheng, Qing Liu, Han Han, Baohua Yang, Yongli Wang, Bo Jiang, Zhengtao WangAbstract:Vasicine (VAS), a potential natural cholinesterase inhibitor, exhibited promising anticholinesterase activity in preclinical models and has been in development for treatment of Alzheimer’s disease. This study systematically investigated the in vitro and in vivo metabolism of VAS in rat using ultra performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 72 metabolites were found based on a detailed analysis of their 1H- NMR and 13C NMR data. Six key metabolites were isolated from rat urine and elucidated as vasicinone, vasicinol, vasicinolone, 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, 9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, and 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-β-D-glucuronide. The metabolic pathway of VAS in vivo and in vitro mainly involved monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of VAS were the 3-hydroxyl group and the C-9 site. All 72 metabolites were found in the urine sample, and 15, 25, 45, 18, and 11 metabolites were identified from rat feces, plasma, bile, rat liver microsomes, and rat primary hepatocyte incubations, respectively. Results indicated that renal clearance was the major excretion pathway of VAS. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of VAS and its main metabolites were also evaluated. The results indicated that although most metabolites maintained potential inhibitory activity against AChE and BChE, but weaker than that of VAS. VAS undergoes metabolic inactivation process in vivo in respect to cholinesterase inhibitory activity.
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Characterization of metabolites of Vasicine in vivo and in vitro in rat by UPLC/Q-TOF.
2015Co-Authors: Wei Liu, Xiaoyuan Shi, Yadi Yang, Xuemei Cheng, Qing Liu, Han Han, Baohua Yang, Yongli Wang, Bo JiangAbstract:Characterization of metabolites of Vasicine in vivo and in vitro in rat by UPLC/Q-TOF.
Dilip M. Mondhe - One of the best experts on this subject based on the ideXlab platform.
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exploring derivatives of quinazoline alkaloid l Vasicine as cap groups in the design and biological mechanistic evaluation of novel antitumor histone deacetylase inhibitors
Journal of Medicinal Chemistry, 2017Co-Authors: Mudassier Ahmad, Mushtaq A. Aga, Javeed Ahmad Bhat, Brijesh Kumar, Abdul Rouf, Neena Capalash, Mubashir J. Mintoo, Ashok Kumar, Priya Mahajan, Dilip M. MondheAbstract:l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-Vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with g...
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Exploring Derivatives of Quinazoline Alkaloid l‑Vasicine as Cap Groups in the Design and Biological Mechanistic Evaluation of Novel Antitumor Histone Deacetylase Inhibitors
2017Co-Authors: Mudassier Ahmad, Mushtaq A. Aga, Javeed Ahmad Bhat, Brijesh Kumar, Abdul Rouf, Neena Capalash, Mubashir J. Mintoo, Ashok Kumar, Priya Mahajan, Dilip M. MondheAbstract:l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-Vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency
Mushtaq A. Aga - One of the best experts on this subject based on the ideXlab platform.
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exploring derivatives of quinazoline alkaloid l Vasicine as cap groups in the design and biological mechanistic evaluation of novel antitumor histone deacetylase inhibitors
Journal of Medicinal Chemistry, 2017Co-Authors: Mudassier Ahmad, Mushtaq A. Aga, Javeed Ahmad Bhat, Brijesh Kumar, Abdul Rouf, Neena Capalash, Mubashir J. Mintoo, Ashok Kumar, Priya Mahajan, Dilip M. MondheAbstract:l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-Vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with g...
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Exploring Derivatives of Quinazoline Alkaloid l‑Vasicine as Cap Groups in the Design and Biological Mechanistic Evaluation of Novel Antitumor Histone Deacetylase Inhibitors
2017Co-Authors: Mudassier Ahmad, Mushtaq A. Aga, Javeed Ahmad Bhat, Brijesh Kumar, Abdul Rouf, Neena Capalash, Mubashir J. Mintoo, Ashok Kumar, Priya Mahajan, Dilip M. MondheAbstract:l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-Vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency
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Vasicine as tridentate ligand for enantioselective addition of diethylzinc to aldehydes
Tetrahedron Letters, 2014Co-Authors: Mushtaq A. Aga, Brijesh Kumar, Abdul Rouf, Bhahwal Ali Shah, Subhash C TanejaAbstract:Abstract The first report of natural l -Vasicine as tridentate chiral ligand for the enantioselective addition of diethylzinc to a variety of aliphatic and aromatic aldehydes is described. The ligand generates R-isomer of the secondary alcohols upto 98% ee. The quinazoline structure possibly imparts rigidity to the ligand and hence, consistently high enantioselectivity. The importance of the quinazoline ring was also supported by the reaction with other related ligands, partially lacking the structural features, thus resulting in poor enantioselectivity.
