Cargando…

Using UPLC-LTQ-Orbitrap-MS and HPLC-CAD to Identify Impurities in Cycloastragenol, Which Is a Pre-Clinical Candidate for COPD

Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease that has become the third leading cause of death worldwide. Cycloastragenol (CAG), which is the genuine sapogenin of the main active triterpene saponins in Astragali radix, is a bioavailable pre-clinical candidate for chronic...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhu, Feng, Zhang, Xiao, Du, Bing-Yuan, Zhu, Xiang-Xia, Zhao, Gui-Fang, Sun, Ying, Yao, Qing-Qiang, Liang, Hong-Bao, Yao, Jing-Chun, Liu, Zhong, Zhang, Gui-Min, Qin, Guo-Fei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10489802/
https://www.ncbi.nlm.nih.gov/pubmed/37687212
http://dx.doi.org/10.3390/molecules28176382
_version_ 1785103698445205504
author Zhu, Feng
Zhang, Xiao
Du, Bing-Yuan
Zhu, Xiang-Xia
Zhao, Gui-Fang
Sun, Ying
Yao, Qing-Qiang
Liang, Hong-Bao
Yao, Jing-Chun
Liu, Zhong
Zhang, Gui-Min
Qin, Guo-Fei
author_facet Zhu, Feng
Zhang, Xiao
Du, Bing-Yuan
Zhu, Xiang-Xia
Zhao, Gui-Fang
Sun, Ying
Yao, Qing-Qiang
Liang, Hong-Bao
Yao, Jing-Chun
Liu, Zhong
Zhang, Gui-Min
Qin, Guo-Fei
author_sort Zhu, Feng
collection PubMed
description Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease that has become the third leading cause of death worldwide. Cycloastragenol (CAG), which is the genuine sapogenin of the main active triterpene saponins in Astragali radix, is a bioavailable pre-clinical candidate for chronic obstructive pulmonary disease (COPD), and it was investigated in our previous study. In order to progress medical research, it was first efficiently produced on a 2.5-kg scale via Smith degradation from astragaloside IV (AS-IV). Simultaneously, since the impurity profiling of a drug is critical for performing CMC documentation in pre-clinical development, a study on impurities was carried out. As these structures do not contain chromophores and possess weak UV absorption characteristics, HPLC-CAD and UPLC-LTQ-Orbitrap-MS were employed to carry out the quality control of the impurities. Then, column chromatography (CC), preparative thin-layer chromatography (PTLC), and crystallization led to the identification of 15 impurities from CAG API. Among these impurities, compounds 1, 4, 9, 10, 14, and 15 were elucidated via spectroscopic analysis, and 2–3, 5–8, and 11–13 were putatively identified. Interestingly, the new compounds 9 and 14 were rare 10, 19-secocycloartane triterpenoids that displayed certain anti-inflammatory activities against LPS-induced lymphocyte cells and CSE-induced MLE-12 cells. Additionally, a plausible structural transformation pathway of the degradation compounds from CAG or AS IV was proposed. The information obtained will provide a material basis to carry out the quality control and clinical safety assurance of API and related prescriptions. Reasonable guidance will also be provided regarding the compounds with weak UV absorption characteristics.
format Online
Article
Text
id pubmed-10489802
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-104898022023-09-09 Using UPLC-LTQ-Orbitrap-MS and HPLC-CAD to Identify Impurities in Cycloastragenol, Which Is a Pre-Clinical Candidate for COPD Zhu, Feng Zhang, Xiao Du, Bing-Yuan Zhu, Xiang-Xia Zhao, Gui-Fang Sun, Ying Yao, Qing-Qiang Liang, Hong-Bao Yao, Jing-Chun Liu, Zhong Zhang, Gui-Min Qin, Guo-Fei Molecules Article Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease that has become the third leading cause of death worldwide. Cycloastragenol (CAG), which is the genuine sapogenin of the main active triterpene saponins in Astragali radix, is a bioavailable pre-clinical candidate for chronic obstructive pulmonary disease (COPD), and it was investigated in our previous study. In order to progress medical research, it was first efficiently produced on a 2.5-kg scale via Smith degradation from astragaloside IV (AS-IV). Simultaneously, since the impurity profiling of a drug is critical for performing CMC documentation in pre-clinical development, a study on impurities was carried out. As these structures do not contain chromophores and possess weak UV absorption characteristics, HPLC-CAD and UPLC-LTQ-Orbitrap-MS were employed to carry out the quality control of the impurities. Then, column chromatography (CC), preparative thin-layer chromatography (PTLC), and crystallization led to the identification of 15 impurities from CAG API. Among these impurities, compounds 1, 4, 9, 10, 14, and 15 were elucidated via spectroscopic analysis, and 2–3, 5–8, and 11–13 were putatively identified. Interestingly, the new compounds 9 and 14 were rare 10, 19-secocycloartane triterpenoids that displayed certain anti-inflammatory activities against LPS-induced lymphocyte cells and CSE-induced MLE-12 cells. Additionally, a plausible structural transformation pathway of the degradation compounds from CAG or AS IV was proposed. The information obtained will provide a material basis to carry out the quality control and clinical safety assurance of API and related prescriptions. Reasonable guidance will also be provided regarding the compounds with weak UV absorption characteristics. MDPI 2023-08-31 /pmc/articles/PMC10489802/ /pubmed/37687212 http://dx.doi.org/10.3390/molecules28176382 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhu, Feng
Zhang, Xiao
Du, Bing-Yuan
Zhu, Xiang-Xia
Zhao, Gui-Fang
Sun, Ying
Yao, Qing-Qiang
Liang, Hong-Bao
Yao, Jing-Chun
Liu, Zhong
Zhang, Gui-Min
Qin, Guo-Fei
Using UPLC-LTQ-Orbitrap-MS and HPLC-CAD to Identify Impurities in Cycloastragenol, Which Is a Pre-Clinical Candidate for COPD
title Using UPLC-LTQ-Orbitrap-MS and HPLC-CAD to Identify Impurities in Cycloastragenol, Which Is a Pre-Clinical Candidate for COPD
title_full Using UPLC-LTQ-Orbitrap-MS and HPLC-CAD to Identify Impurities in Cycloastragenol, Which Is a Pre-Clinical Candidate for COPD
title_fullStr Using UPLC-LTQ-Orbitrap-MS and HPLC-CAD to Identify Impurities in Cycloastragenol, Which Is a Pre-Clinical Candidate for COPD
title_full_unstemmed Using UPLC-LTQ-Orbitrap-MS and HPLC-CAD to Identify Impurities in Cycloastragenol, Which Is a Pre-Clinical Candidate for COPD
title_short Using UPLC-LTQ-Orbitrap-MS and HPLC-CAD to Identify Impurities in Cycloastragenol, Which Is a Pre-Clinical Candidate for COPD
title_sort using uplc-ltq-orbitrap-ms and hplc-cad to identify impurities in cycloastragenol, which is a pre-clinical candidate for copd
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10489802/
https://www.ncbi.nlm.nih.gov/pubmed/37687212
http://dx.doi.org/10.3390/molecules28176382
work_keys_str_mv AT zhufeng usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd
AT zhangxiao usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd
AT dubingyuan usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd
AT zhuxiangxia usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd
AT zhaoguifang usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd
AT sunying usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd
AT yaoqingqiang usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd
AT lianghongbao usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd
AT yaojingchun usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd
AT liuzhong usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd
AT zhangguimin usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd
AT qinguofei usinguplcltqorbitrapmsandhplccadtoidentifyimpuritiesincycloastragenolwhichisapreclinicalcandidateforcopd