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Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS
The neuroprotective evaluation of ligustrazine derivatives has become a research focus all over the world. A novel ligustrazine derivative, (3,5,6-Trimethylpyrazin-2-yl)methyl(E)-3-(4-((3,5,6-trimethylpyrazin-2-l)methoxy)phenyl)acrylate (T-CA), has shown protective effects against CoCl(2)-induced ne...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100194/ https://www.ncbi.nlm.nih.gov/pubmed/29751639 http://dx.doi.org/10.3390/molecules23051154 |
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author | Zhang, Xinyu Zhao, Rui Chen, Meng Ma, Tao Wu, Gaorong Xue, Nannan Li, Guoliang Wang, Hui Fang, Kang Zhang, Wenxi Wang, Penglong Lei, Haimin |
author_facet | Zhang, Xinyu Zhao, Rui Chen, Meng Ma, Tao Wu, Gaorong Xue, Nannan Li, Guoliang Wang, Hui Fang, Kang Zhang, Wenxi Wang, Penglong Lei, Haimin |
author_sort | Zhang, Xinyu |
collection | PubMed |
description | The neuroprotective evaluation of ligustrazine derivatives has become a research focus all over the world. A novel ligustrazine derivative, (3,5,6-Trimethylpyrazin-2-yl)methyl(E)-3-(4-((3,5,6-trimethylpyrazin-2-l)methoxy)phenyl)acrylate (T-CA), has shown protective effects against CoCl(2)-induced neurotoxicity in a differentiated PC12 cell model and middle cerebral artery occlusion (MCAO) model in our previous studies. However, nearly none of the parent drugs existed after rapid metabolism due to uncertain reasons. Thus, the fragmentation regularities of mass spectra, and metabolites, of T-CA in rats were examined using liquid chromatography-electrospray ionizationion trap mass spectrometry (LC/LTQ-Orbitrap MS) in this research. The main fragment ion, mass spectrum characteristics, and the structural information were elucidated. When compared with a blank sample, we identified five kinds of T-CA metabolites, including three phase I metabolites and two phase II metabolites. The results showed that the metabolic pathways of T-CA in rats via oral administration were hydrolysis (ether bond rupture, ester bond rupture), oxidation, reduction, glucose aldehyde acidification, etc. In addition, three main metabolites were synthesized and their structures were identified by superconducting high-resolution NMR and high-resolution mass spectroscopy (HR-MS). The neuroprotective activity of these metabolites was validated in a PC12 cell model. One of the metabolites (M2) showed significant activity (EC(50) = 9.67 μM), which was comparable to the prototype drug T-CA (EC(50) = 7.97 μM). The current study provides important information for ligustrazine derivatives, pertaining to the biological conversion process in vivo. |
format | Online Article Text |
id | pubmed-6100194 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-61001942018-11-13 Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS Zhang, Xinyu Zhao, Rui Chen, Meng Ma, Tao Wu, Gaorong Xue, Nannan Li, Guoliang Wang, Hui Fang, Kang Zhang, Wenxi Wang, Penglong Lei, Haimin Molecules Article The neuroprotective evaluation of ligustrazine derivatives has become a research focus all over the world. A novel ligustrazine derivative, (3,5,6-Trimethylpyrazin-2-yl)methyl(E)-3-(4-((3,5,6-trimethylpyrazin-2-l)methoxy)phenyl)acrylate (T-CA), has shown protective effects against CoCl(2)-induced neurotoxicity in a differentiated PC12 cell model and middle cerebral artery occlusion (MCAO) model in our previous studies. However, nearly none of the parent drugs existed after rapid metabolism due to uncertain reasons. Thus, the fragmentation regularities of mass spectra, and metabolites, of T-CA in rats were examined using liquid chromatography-electrospray ionizationion trap mass spectrometry (LC/LTQ-Orbitrap MS) in this research. The main fragment ion, mass spectrum characteristics, and the structural information were elucidated. When compared with a blank sample, we identified five kinds of T-CA metabolites, including three phase I metabolites and two phase II metabolites. The results showed that the metabolic pathways of T-CA in rats via oral administration were hydrolysis (ether bond rupture, ester bond rupture), oxidation, reduction, glucose aldehyde acidification, etc. In addition, three main metabolites were synthesized and their structures were identified by superconducting high-resolution NMR and high-resolution mass spectroscopy (HR-MS). The neuroprotective activity of these metabolites was validated in a PC12 cell model. One of the metabolites (M2) showed significant activity (EC(50) = 9.67 μM), which was comparable to the prototype drug T-CA (EC(50) = 7.97 μM). The current study provides important information for ligustrazine derivatives, pertaining to the biological conversion process in vivo. MDPI 2018-05-11 /pmc/articles/PMC6100194/ /pubmed/29751639 http://dx.doi.org/10.3390/molecules23051154 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zhang, Xinyu Zhao, Rui Chen, Meng Ma, Tao Wu, Gaorong Xue, Nannan Li, Guoliang Wang, Hui Fang, Kang Zhang, Wenxi Wang, Penglong Lei, Haimin Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS |
title | Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS |
title_full | Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS |
title_fullStr | Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS |
title_full_unstemmed | Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS |
title_short | Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS |
title_sort | novel neuroprotective lead compound ligustrazine derivative mass spectrometry fragmentation rule and metabolites in rats by lc/ltq-orbitrap ms |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100194/ https://www.ncbi.nlm.nih.gov/pubmed/29751639 http://dx.doi.org/10.3390/molecules23051154 |
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