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

Xueyan Hou, Feng Wu, Meng Zhou, Hao Luo, Wenjuan Zhang, Xuan Han, Guoyi Yan, Jianyou Shi, Rui Li
2013 Huaxue xuebao  
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
more » ... on 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 R 2 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-H 2 O] + . 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 H 2 O 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.
doi:10.6023/a13030320 fatcat:ae6ndawjsjcrjhb4m3y6qybhoi