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Molecules 2018, 23(5), 1154; https://doi.org/10.3390/molecules23051154

Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS

School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China
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Academic Editor: Marcello Iriti
Received: 15 April 2018 / Revised: 7 May 2018 / Accepted: 8 May 2018 / Published: 11 May 2018
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Abstract

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 CoCl2-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 (EC50 = 9.67 μM), which was comparable to the prototype drug T-CA (EC50 = 7.97 μM). The current study provides important information for ligustrazine derivatives, pertaining to the biological conversion process in vivo. View Full-Text
Keywords: liquid chromatography-electrospray ionizationion trap mass spectrometry (LC/LTQ-Orbitrap MS); fragmentation regularities; ligustrazine derivative metabolites; neuroprotective activity liquid chromatography-electrospray ionizationion trap mass spectrometry (LC/LTQ-Orbitrap MS); fragmentation regularities; ligustrazine derivative metabolites; neuroprotective activity
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Zhang, X.; Zhao, R.; Chen, M.; Ma, T.; Wu, G.; Xue, N.; Li, G.; Wang, H.; Fang, K.; Zhang, W.; Wang, P.; Lei, H. Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS. Molecules 2018, 23, 1154.

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