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

doi:10.6023/A13030320

Acta Chimica Sinica ›› 2013, Vol. 71 ›› Issue (08): 1161-1166.DOI: 10.6023/A13030320 Previous Articles Next Articles

Article

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).

1. Study of Fragmentation Mechanisms of Pyrrolo[3,4-c]pyrazole Derived Aurora Kinase Inhibitors by ESI-QTOF-MS/MS.PDF(323KB)

Abstract

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

Cite this article

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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[1] Rita, H.; Madhu, K.; Jirina, T.; Peter, H.; Marian, H.; Suresh, J. G.; Hana, K. J. Proteome Res. 2013, 12, 455.

[2] Xia, L. P.; Zhou, F. F.; Yang, M. T.; Liu, Q. Chin. J. Cancer 2009, 28, 668. (夏良平, 周菲菲, 杨名添, 刘强, 癌症, 2009, 28, 668.)

[3] Jane, E. V. Nature 2011, 469, 314.

[4] Crane, R.; Gadea, B.; Littlepage, L.; Wu, H.; Ruderman, J. V. Biol. Cell 2004, 96, 215.

[5] Nicholas, K.; Stephen, T. Nat. Rev. Cancer 2004, 4, 927.

[6] Fancelli, D.; Berta, D.; Bindi, S.; Cameron, A.; Cappella, P.; Carpinelli, P.; Catana, C.; Forte, B.; Giordano, P.; Giorgini, M. L.; Mantegani, S.; Marsiglio, A.; Meroni, M.; Moll, J.; Pittalà, V.; Roletto, F.; Severino, D.; Soncini, C.; Storici, P.; Tonani, R.; Varasi, M.; Vulpetti, A.; Vianello, P. J. Med. Chem. 2005, 48, 3080.

[7] Lin, Y.; Richards, F. M.; Krippendorff, B. F.; Bramhall, J. L.; Harrington, J. A.; Bapiro, T. E.; Robertson, A.; Zheleva, D.; Jodrell, D. I. Br. J. Cancer 2012, 107, 1692.

[8] Carpinelli, P.; Ceruti, R.; Giorgini, M. L.; Cappella, P.; Gianellini, L.; Croci, V.; Degrassi, A.; Texido, G.; Rocchetti, M.; Vianello, P.; Rusconi, L.; Storici, P.; Zugnoni, P.; Arrigoni, C.; Soncini, C.; Alli, C.; Patton, V.; Marsiglio, A.; Ballinari, D.; Pesenti, E.; Fancelli, D.; Moll, J. Mol. Cancer Ther. 2007, 6, 3158.

[9] Harrington, E. A.; Bebbington, D.; Moore, J.; Rasmussen, R. K.; Ajose-Adeogun, A. O.; Nakayama, T.; Graham, J. A.; Demur, C.; Hercend, T.; Diu-Hercend, A.; Su, M.; Golec, J. M.; Miller, K. M. Nat. Med. 2004, 10, 262.

[10] Fancelli, D.; Moll, J.; Varasi, M.; Bravo, R.; Artico, R.; Berta, D.; Bindi, S.; Cameron, A.; Candiani, I.; Cappella, P.; Carpinelli, P.; Croci, W.; Forte, B.; Giorgini, M. L.; Klapwijk, J.; Marsiglio, A.; Pesenti, E.; Rocchetti, M.; Roletto, F.; Severino, D.; Soncini, C.; Storici, P.; Tonani, R.; Zugnoni, P.; Vianello, P. J. Med. Chem. 2006, 49, 7247.

[11] Wang, L. Y.; Wang, Z.; Yan, A. X.; Yuan, Q. P. Mol. Inf. 2011, 30, 35.

[12] Fei, F.; Lim, M.; Schmidhuber, S.; Moll, J.; Groffen, J.; Heisterkamp, N. Mol. Cancer 2012, 11, 1.

[13] Benten, D.; Keller, G.; Quaas, A.; Schrader, J.; Gontarewicz, A.; Balabanov, S.; Braig, M.; Wege, H.; Moll, J.; Lohse, A. W.; Brummendorf, T. H. Neoplasia 2009, 11, 934.

[14] Li, R.; Wang, X.; Zhou, Y.; Cai, M.; Ding, L. J. Mass Spectrom. 2007, 42, 335.

[15] Ivana, S.; Igor, B.; Goran, K.; Miroslav, B. Rapid Commun. Mass Spectrom. 2012, 26, 1023.

[16] Zhang, J. D.; Wang, H. F.; Xue, X. Y.; Zhang, Y. W.; Cheng, X. L. Acta Chim. Sinica 2012, 70, 2543. (张吉东, 王海锋, 薛新英, 张岩文, 程新路, 化学学报, 2012, 70, 2543.)

[17] Wang, D. D.; Gong, C. M.; Zhu, Q.; Wang, J. L.; Li, X. Y. Acta Chim. Sinica 2013, 71, 88. (王丹丹, 巩春明, 朱权, 王健礼, 李象远, 化学学报, 2013, 71, 88.)

[18] Chai, Y. F.; Gan, S. F.; Pan, Y. J. Acta Chim Sinica 2012, 70, 1805. (柴云峰, 甘世凤, 潘远江, 化学学报, 2012, 70, 1805.)

[19] Alex, A.; Harvey, S.; Parsons, T.; Pullen, F. S.; Wrightm, P.; Riley, J. A. Rapid Commun. Mass Spectrom. 2009, 23, 2619.

[20] Bowie, J. H.; Brinkworth, C. S.; Dua, S. Mass Spectrom. Rev. 2002, 21, 87.

[21] Bilusich, D.; Bowie, J. H. Mass Spectrom. Rev. 2009, 28, 20.

[22] Raftery, M. J.; Bowie, J. H. Int. J. Mass Spectrom. Ion Processes 1988, 85, 167.

[23] Thielking, G.; Filges, U.; Grutzmacher, H. F. J. Am. Soc. Mass Spectrom. 1992, 3, 417.

[24] Tu, Y. P. Int. J. Mass Spectrom. 2012, 316, 40.

[25] Gianluca, G.; Antonio, P. P.; Andrea, P.; Silvestre, B. J. Am. Soc. Mass Spectrom. 2008, 19, 686.

[26] Liu, D. F.; Thomas, W.; Michael, T. B. Int. J. Mass Spectrom. 2004, 236, 81.

[27] Mario, T.; Maxie, K.; Nils, S.; Wilhelm, S. J. Am. Soc. Mass Spectrom. 2008, 19, 151.

[28] Woenckhaus, J. Int. J. Mass Spectrom. 2002, 213, 9.

[29] Guo, M. Q.; Song, F. R.; Chen, M. L.; Bai, Y.; Liu, Z. Q.; Liu, S. Y. Chem. J. Chin. Univ. 2003, 24, 1577. (郭明全, 宋凤瑞, 陈貌连, 白玉, 刘志强, 刘淑莹, 高等学校化学学报, 2003, 24, 1577.)

[30] Hélène, L.; Peter, J. D.; Albert, J. R.; Fred, A. M. Anal. Biochem. 1998, 255, 74.

[31] Li, Y. G.; Lin, Q. M.; Wang, H.; Dai, L.; Liu, J. C. J. XiaMen Univ. 1992, 31, 397. (李玉桂, 林庆梅, 王浩, 戴亮, 刘家础, 厦门大学学报, 1992, 31, 397.)

[32] Giorgi, G.; Antonio, P. P.; Andream, P.; Silvestre, B. J. Mass Spectrom. 2008, 43, 265.

[33] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; et al.; Pople, J. A. Gaussian 03, Revision B, Gaussian, Inc., Pittsburgh, PA, 2003.

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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