吡咯并[3,4-c]吡唑衍生的Aurora激酶抑制剂在电喷雾质谱中的裂解规律研究

doi:10.6023/A13030320

化学学报 ›› 2013, Vol. 71 ›› Issue (08): 1161-1166.DOI: 10.6023/A13030320 上一篇下一篇

研究论文

吡咯并[3,4-c]吡唑衍生的Aurora激酶抑制剂在电喷雾质谱中的裂解规律研究

侯雪艳^a, 武锋^a, 周孟^a, 罗浩^a, 张文娟^a, 韩璇^a, 闫国毅^a, 师健友^b, 李锐^a

a 四川大学生物治疗国家重点实验室成都 610041;
b 四川省医学科学院·四川省人民医院药剂科成都 610072

投稿日期:2013-03-21 发布日期:2013-05-16
通讯作者: 师健友;李锐, E-mail: lirui@scu.edu.cn; Tel.: 028-85164063; Fax: 028-85164060 E-mail:lirui@scu.edu.cn
基金资助:
项目受国家自然科学基金(No. 30901743)、教育部博士点新教师基金(No. 20090181120113)以及国家科技重大专项(No. 2012ZX09103101-022)资助.

Study of Fragmentation Mechanisms of Pyrrolo[3,4-c]pyrazole Derived Aurora Kinase Inhibitors by ESI-QTOF-MS/MS

Hou Xueyan^a, Wu Feng^a, Zhou Meng^a, Luo Hao^a, Zhang Wenjuan^a, Han Xuan^a, Yan Guoyi^a, Shi Jianyou^b, Li Rui^a

a State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041;
b Department of Pharmacy, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu 610072

Received:2013-03-21 Published:2013-05-16
Supported by:
Project supported by the National Natural Science Foundation of China (No. 30901743), the Doctoral Fund of Ministry of Education (No. 20090181120113) and the National Key Program of China (No. 2012ZX09103101-022).

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摘要/Abstract

吡咯并[3,4-c]吡唑衍生的Aurora激酶抑制剂是具有良好开发前景的新型抗肿瘤药物之一. 采用电喷雾-四级杆飞行时间串联质谱技术, 对4种吡咯并[3,4-c]吡唑衍生的Aurora激酶抑制剂在电喷雾质谱中的裂解途径及其碎片离子结构进行研究. 实验结果表明: 吡咯并[3,4-c]吡唑衍生物拥有4个可能的质子化模式, 不同的质子化作用会产生不同的碎片离子, 且吡咯并[3,4-c]吡唑衍生物N(5)—CO键断裂所产生的碎片离子相对丰度较高, 可以作为药物代谢动力学及酶学水平研究中质谱的特征性碎片离子. 需要指出的是, 化合物3, 4能够分别丢失一分子水形成碎片离子[M+H-H₂O]⁺, 根据高分辨质谱和理论计算结果我们推测该过程是由质子化作用发生在酰胺氧原子上引发的, 而CID条件下N(5)—CO键的进一步断裂可产生相对丰度较高的碎片离子.

关键词: Aurora激酶抑制剂, 吡咯并[3,4-c]吡唑衍生物, ESI-QTOF-MS/MS, 裂解规律, 同分异构体

Aurora kinase inhibitors represent an emerging class of drugs against various tumors such as acute lymphoblastic leukemia and hepatocellular carcinomain. A variety of drug candidates have been developed and investigated including a group that comprises pyrrolo[3,4-c]pyrazole core such as danusertib (PHA-739358). Due to their novelty and medicinal purpose, four pyrrolo[3,4-c]pyrazole derivatives were synthesized and were conducted to provide information on typical fragmentation pathways by electrospray ionization (ESI) and collision induced dissociation (CID). The product ions derived from protonated molecules were investigated by ESI-quadrupole time of flight tandem mass spectrometry (QTOF-MS/MS) and theoretical methods. It should be pointed that four favorite protonation modes were observed and each mode had its own characteristic fragmentation pathways. Major and general findings contained the elimination of R² group from[M+H]⁺and the dissociation of C(4)—N(5), C(6)—N(5) bonds, which was depended on the most favorable protonation mode, while the other product ions were formed based on the other protonation modes. Interestingly, the loss of 18 Da from potential aurora kinase inhibitors 3, 4 was occurred, even though there was no free hydroxyl group. Accurate mass measurements have allowed us to determine that a molecule of water was eliminated from protonated molecules directly. This process may start with the most favorable protonation mode; then a conformational change implied by rotation of the acetyl group around the internal 3-amide bond of protonated molecules occurred to yield an intermediate. Followed by the hydrogen transference and elongation of C—O bond, a molecule of water was expelled to give the product ion[M+H-H₂O]⁺. The process was supported by the theoretical calculations. Additionally, two other special product ions were formed according to the hydration reaction. It was viewed that the origin of H₂O was the elimination of protonated molecules. These observations may provide some applications for monitoring and characterization of their presence and metabolites in complex mixtures, such as urine and blood.

Key words: aurora kinase inhibitors, pyrrolo[3,4-c]pyrazole derivatives, ESI-QTOF-MS/MS, fragmentation mechanisms, isomers

引用此文

侯雪艳, 武锋, 周孟, 罗浩, 张文娟, 韩璇, 闫国毅, 师健友, 李锐. 吡咯并[3,4-c]吡唑衍生的Aurora激酶抑制剂在电喷雾质谱中的裂解规律研究[J]. 化学学报, 2013, 71(08): 1161-1166.

Hou Xueyan, Wu Feng, Zhou Meng, Luo Hao, Zhang Wenjuan, Han Xuan, Yan Guoyi, Shi Jianyou, Li Rui. Study of Fragmentation Mechanisms of Pyrrolo[3,4-c]pyrazole Derived Aurora Kinase Inhibitors by ESI-QTOF-MS/MS[J]. Acta Chimica Sinica, 2013, 71(08): 1161-1166.

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吡咯并[3,4-c]吡唑衍生的Aurora激酶抑制剂在电喷雾质谱中的裂解规律研究

Study of Fragmentation Mechanisms of Pyrrolo[3,4-c]pyrazole Derived Aurora Kinase Inhibitors by ESI-QTOF-MS/MS

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