芥子气三肽加合物合成新路线开发及在确证分析中的应用

引用本文: 杨展, 刘玉龙, 陈佳, 吴剑峰, 何跃忠, 谢剑炜. 芥子气三肽加合物合成新路线开发及在确证分析中的应用[J]. 分析化学, 2022, 50(1): 136-144. doi: 10.19756/j.issn.0253-3820.210454 shu

Citation: YANG Zhan, LIU Yu-Long, CHEN Jia, WU Jian-Feng, HE Yue-Zhong, XIE Jian-Wei. Development of a New Synthetic Route of Tripeptide-adduct of Sulfur Mustard Exposure and Application in Confirmatory Analysis[J]. Chinese Journal of Analytical Chemistry, 2022, 50(1): 136-144. doi: 10.19756/j.issn.0253-3820.210454 shu

芥子气三肽加合物合成新路线开发及在确证分析中的应用

杨展 ^1,2, ,
刘玉龙 ^2, ,
陈佳 ^2, ,
吴剑峰 ^{2,
,} ,
何跃忠 ^1, ,
谢剑炜 ^2,

1.
军事科学院军事医学研究院, 北京 100850;
2.
军事科学院军事医学研究院毒物药物研究所, 抗毒药物与毒理学国家重点实验室, 北京 100850

通讯作者: 吴剑峰,E-mail:ammswjf@163.com

基金项目:
国家重点研发计划（Nos.2018YFC1602600，2020YFF0305000）资助。

摘要: 芥子气（Sulfur mustard，SM）是一种典型的难防难治化学战剂，生物体SM暴露后，除自身发生氧化水解代谢反应外，还会与体内的蛋白质、谷胱甘肽及DNA等生成一系列的加合物。白蛋白在血浆中丰度较高，芥子气与其34位半胱氨酸（Cys-34）结合形成加合物，再经蛋白酶K水解后生成三肽加合物（HETE-Cys-Pro-Phe，HETE-CPF）。HETE-CPF半衰期长、稳定性好，是溯源SM暴露最有效，也是最重要的生物标志物。本研究以易获取的商品化试剂氯乙醇为起始原料，开发了一条新的HETE-CPF合成方法。相比于原有以2-氯乙基巯基乙醇为起始原料的合成方法，新方法副反应更少、纯化更简便。在此基础上建立了可用于全血样本中HETE-CPF的高灵敏分析检测方法，检测灵敏度可达2 ng/mL。同时，还鉴定出大鼠经尾静脉注射SM暴露后，其与血浆白蛋白形成的暴露标志物与人源血浆差异显著，为HETE-Cys-Pro-Tyr （HETE-CPY），并非HETE-CPF，两者白蛋白一级序列差异是导致标志物不同的根本原因。

关键词:

English

Development of a New Synthetic Route of Tripeptide-adduct of Sulfur Mustard Exposure and Application in Confirmatory Analysis

1.
Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China;
2.
State Key Laboratory of Toxicology and Medical Countermeasures and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China

Corresponding author: WU Jian-Feng, ammswjf@163.com

Received Date: 21 April 2021
Revised Date: 16 October 2021
Fund Project:
Supported by the National Key Research and Development Program of China (Nos.2018YFC1602600, 2020YFF0305000).

Abstract: Sulfurmustard (SM) is a typical representative of highly-toxic chemical warfare agent that is difficult to be prevented and treated. SM could produce various biomarkers with protein, glutathione and DNA, etc, besides oxidative and hydrolytic metabolism. The tripeptide-adduct hydroxyethylthioethyl-Cys-Pro-Pro (HETE-CPF) originating from Cys-34 on the human serum albumin (HSA) is a very important retrospective biomarker, which is usually used to identify SM exposure due to its long half-life and good stability. In this work, a novel synthetic route of HETE-CPF was developed with chloroethanol as the starting material. Compared with the original synthetic route using 2-chloroethyl mercaptoethanol as the starting material, the new synthetic method had less side reactions, higher yield and easier purification. Furthermore, a highly sensitive analysis method for HETE-CPF in whole blood samples was established, and the detection sensitivity was up to 2 ng/mL, which was enough to identify human plasma sample after exposure to SM. Meanwhile, it was also identified that after SM exposure via caudal vein in rats, the exposure biomarkers formed with plasma albumin were significantly different from those of human plasma, which was HETE-Cys-Pro-Tyr (HETE-CPY), not HETE-CPF. The fundamental reason might be due to their different primary sequence of albumin.

Key words:

1. [1]
  BORAK J, SIDELL F R. Ann. Emerg. Med., 1992, 21(3):303-308.BORAK J, SIDELL F R. Ann. Emerg. Med., 1992, 21(3):303-308.
2. [2]
  BERGMAN N H, ANDERSON E C, SWENSON E E, NIEMEYER M M, MIYOSHI A D, HANNA P C. Int. Legal Mate., 1993, 32(3):800-873.BERGMAN N H, ANDERSON E C, SWENSON E E, NIEMEYER M M, MIYOSHI A D, HANNA P C. Int. Legal Mate., 1993, 32(3):800-873.
3. [3]
  NOORT D, VANDER SCHANS M J, BENSCHOP H P. Biomonitoring of Exposure to Chemical Warfare Agents. Springer Dordrecht, 2006:21-26.NOORT D, VANDER SCHANS M J, BENSCHOP H P. Biomonitoring of Exposure to Chemical Warfare Agents. Springer Dordrecht, 2006:21-26.
4. [4]
  PANAHI Y, GHOLAMI N, GHOJAZADEH M, MOSLEMI F, NAGHAVI-BEHZAD M, AZAMI-AGHDASH S, GHAFFARI A, PIRI R. Asian Pac. J. Cancer Prev., 2015, 16(17):7567-7573.PANAHI Y, GHOLAMI N, GHOJAZADEH M, MOSLEMI F, NAGHAVI-BEHZAD M, AZAMI-AGHDASH S, GHAFFARI A, PIRI R. Asian Pac. J. Cancer Prev., 2015, 16(17):7567-7573.
5. [5]
  NOORT D, BENSCHOP H P, BLACK R M. Toxicol. Appl. Pharmacol., 2002, 184(2):116-126.NOORT D, BENSCHOP H P, BLACK R M. Toxicol. Appl. Pharmacol., 2002, 184(2):116-126.
6. [6]
  PEARSON G S. The United Nations Secretary-General Investigations in Iran and Iraq. The Search for Iraq's Weapons of Mass Destruction London:Palgrave Macmillan, 2005:9-25.PEARSON G S. The United Nations Secretary-General Investigations in Iran and Iraq. The Search for Iraq's Weapons of Mass Destruction London:Palgrave Macmillan, 2005:9-25.
7. [7]
  NOURANI M R, MAOODZADEH H H, AZIMZADEH J S, IMANIFOOLADI A A. J. Recept. Signal Transduct. Res., 2017, 37(2):200-216.NOURANI M R, MAOODZADEH H H, AZIMZADEH J S, IMANIFOOLADI A A. J. Recept. Signal Transduct. Res., 2017, 37(2):200-216.
8. [8]
  WHEELER G P. Cancer Res., 1962, 22:651-688.WHEELER G P. Cancer Res., 1962, 22:651-688.
9. [9]
  QI M, XU B, WU J, ZHANG Y, ZONG C, CHEN J, GUO L, XIE J. J. Chromatogr. B, 2016, 1028:42-50.QI M, XU B, WU J, ZHANG Y, ZONG C, CHEN J, GUO L, XIE J. J. Chromatogr. B, 2016, 1028:42-50.
10. [10]
  XU H, NIE Z, ZHANG Y, LI C, YUE L, YANG W, CHEN J, DONG Y, LIU Q, LIN Y, WU B, FENG J,LI H, GUO L, XIE J. Toxicol. Rep., 2014, 1:533-543.XU H, NIE Z, ZHANG Y, LI C, YUE L, YANG W, CHEN J, DONG Y, LIU Q, LIN Y, WU B, FENG J,LI H, GUO L, XIE J. Toxicol. Rep., 2014, 1:533-543.
11. [11]
  PANAHI Y, ABDOLGHAFFARI A H, SAHEBKAR A. J. Cell. Biochem., 2018, 119(1):197-206.PANAHI Y, ABDOLGHAFFARI A H, SAHEBKAR A. J. Cell. Biochem., 2018, 119(1):197-206.
12. [12]
  ZHANG Lin, MA Ming-Ying, LI Bao-Qiang, KONG Jing-Lin, ZHANG Si-Chun, ZHANG Xin-Rong. Chin. J. Anal. Chem., 2020, 48(10):1416-1421. 张琳, 马明英, 李宝强, 孔景临, 张四纯, 张新荣. 分析化学, 2020, 48(10):1416-1421.
13. [13]
  NOORT D, HULST A G, TRAP H C, DE JONG L P, BENSCHOP H P. Arch. Toxicol., 1997, 71(3):171-178.NOORT D, HULST A G, TRAP H C, DE JONG L P, BENSCHOP H P. Arch. Toxicol., 1997, 71(3):171-178.
14. [14]
  JOHN H, WILLOH S, HORMANN P, SIEGERT M, VONDRAN A, THIERMANN H. Anal. Chem., 2016,88(17):8787-8794.JOHN H, WILLOH S, HORMANN P, SIEGERT M, VONDRAN A, THIERMANN H. Anal. Chem., 2016,88(17):8787-8794.
15. [15]
  LIU C, LIANG L, XIANG Y, YU H, ZHOU S, XI H, LIU S, LIU J. Anal. Bioanal. Chem., 2015, 407(23):7037-7046.LIU C, LIANG L, XIANG Y, YU H, ZHOU S, XI H, LIU S, LIU J. Anal. Bioanal. Chem., 2015, 407(23):7037-7046.
16. [16]
  PANTAZIDES B G, CROW B S, GARTON J W, QUINONES-GONZALEZ J A, BLAKE T A, THOMAS J D, JOHNSON R C. Chem. Res. Toxicol., 2015, 28(2):256-261.PANTAZIDES B G, CROW B S, GARTON J W, QUINONES-GONZALEZ J A, BLAKE T A, THOMAS J D, JOHNSON R C. Chem. Res. Toxicol., 2015, 28(2):256-261.
17. [17]
  ANDACHT T M, PANTAZIDES B G, CROW B S, FIDDER A, NOORT D, THOMAS J D, BLAKE T A, JOHNSON R C. J. Anal. Toxicol., 2014, 38(1):8-15.ANDACHT T M, PANTAZIDES B G, CROW B S, FIDDER A, NOORT D, THOMAS J D, BLAKE T A, JOHNSON R C. J. Anal. Toxicol., 2014, 38(1):8-15.
18. [18]
  BAO Y, LIU Q, CHEN J, LIN Y, WU B, XIE J. J. Chromatogr. A, 2012, 1229:164-171.BAO Y, LIU Q, CHEN J, LIN Y, WU B, XIE J. J. Chromatogr. A, 2012, 1229:164-171.
19. [19]
  YANG Liu, LIU Qin, GUO Lei, XIE Jian-Wei. Modern Instrum. Med. Treat., 2015, 2:67-69. 杨柳, 刘勤, 郭磊, 谢剑炜. 现代仪器与医疗, 2015, 2:67-69.
20. [20]
  RAO M K, SHARMA M, RAZA S K, JAISWAL D K. Phosphorus, Sulfur Silicon Relat. Elem., 2003, 178(3):559-566.RAO M K, SHARMA M, RAZA S K, JAISWAL D K. Phosphorus, Sulfur Silicon Relat. Elem., 2003, 178(3):559-566.
21. [21]
  TROESTER M A, LINDSTROM A B, WAIDYANATHA S, KUPPER L L, RAPPAPORT S M. Toxicol. Sci., 2002, 68(2):314-321.TROESTER M A, LINDSTROM A B, WAIDYANATHA S, KUPPER L L, RAPPAPORT S M. Toxicol. Sci., 2002, 68(2):314-321.

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通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

芥子气三肽加合物合成新路线开发及在确证分析中的应用

通讯作者: 吴剑峰,E-mail:ammswjf@163.com

English

Development of a New Synthetic Route of Tripeptide-adduct of Sulfur Mustard Exposure and Application in Confirmatory Analysis

Corresponding author: WU Jian-Feng, ammswjf@163.com

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通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

芥子气三肽加合物合成新路线开发及在确证分析中的应用

通讯作者: 吴剑峰,E-mail:ammswjf@163.com

English

Development of a New Synthetic Route of Tripeptide-adduct of Sulfur Mustard Exposure and Application in Confirmatory Analysis

Corresponding author: WU Jian-Feng, ammswjf@163.com

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南： 你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

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