Gas‐phase fragmentation of protonated piplartine and its fungal metabolites using tandem mass spectrometry and computational chemistry

Abstract

Piplartine, an alkaloid produced by plants in the genus Piper, displays promising anticancer activity. Understanding the gas-phase fragmentation of piplartine by electrospray ionization tandem mass spectrometry can be a useful tool to characterize biotransformed compounds produced by in vitro and in vivo metabolism studies. As part of our efforts to understand natural product fragmentation in electrospray ionization tandem mass spectrometry, the gas-phase fragmentation of piplartine and its two metabolites 3,4-dihydropiplartine and 8,9-dihydropiplartine, produced by the endophytic fungus Penicillium crustosum VR4 biotransformation, were systematically investigated. Proposed fragmentation reactions were supported by ESI-MS/MS data and computational thermochemistry. Cleavage of the C-7 and N-amide bond, followed by the formation of an acylium ion, were characteristic fragmentation reactions of piplartine and its analogs. The production of the acylium ion was followed by three consecutive and competitive reactions that involved methyl and methoxyl radical eliminations and neutral CO elimination, followed by the formation of a four-member ring with a stabilized tertiary carbocation. The absence of a double bond between carbons C-8 and C-9 in 8,9-dihydropiplartine destabilized the acylium ion and resulted in a fragmentation pathway not observed for piplartine and 3,4-dihydropiplartine. These results contribute to the further understanding of alkaloid gas-phase fragmentation and the future identification of piplartine metabolites and analogs using tandem mass spectrometry techniques. Copyright © 2017 John Wiley & Sons, Ltd.

Fragmentation pattern of amides by EI and HRESI: study of protonation sites using DFT-3LYP data

“…1 and 2). [14][15][16] This peculiar cleavage, observed in the a,b-unsaturated piperamides is unusual in aliphatic amides, in which McLafferty rearrangement is preferable wherever g-hydrogen to the carbonyl is available. Additionally, the a-cleavage of secondary and tertiary aliphatic amides and the formation of acylium cations can also be used to support the characterization of amides.…”

“…The conjugation between the amide carbonyl and the b double bond reinforced by the presence of an aryl group at the g or 5 positions from the carbonyl could account for preferable N-CO fragmentation. 15,16 Herein, several analogs synthesized were subjected to mass spectrometry studies to determine whether the N-CO a-cleavage could be generalized and used as a criteria for the rapid identication of piperamides. Computational studies (proton affinity and bond energies) were carried out to verify the N-CO a-cleavage.…”

Combined use of tandem mass spectrometry and computational chemistry to study 2H‐chromenes from Piper aduncum

“…Among all the methods capable of determining the identity of organic compounds, mass spectrometry (MS) has been a valuable technique . The development of soft ionization sources, such as electrospray ionization (ESI), as well as the advances of tandem mass spectrometry (MS/MS), have contributed to analyzing and explaining the fragmentation patterns of a number of secondary metabolites . These techniques have many advantages over other methods widely used, since it is possible to study the fragmentation mechanisms of the diagnostic ions to provide information in assigning likely chemical structures to those unknown in metabolomic, biosynthetic, and biotechnological studies …”

Fragmentation pathways and differentiation of positional isomers of sorafenib and structural analogues by ESI‐IT‐MSn and ESI‐Q‐TOF‐MS/MS coupled with DFT calculations

“…The complementation of ESI‐IT‐MS n and ESI‐Q‐TOF‐MS/MS could greatly facilitate the speculation of fragmentation pathways, which is essential for chemical structure recognition of unknown compounds . Moreover, computational quantum calculation provides theoretical data to further verify the reasonability of the speculated fragmentation pathways …”

“…16 Moreover, computational quantum calculation provides theoretical data to further verify the reasonability of the speculated fragmentation pathways. 17,18 In this work, the fragmentation pathways of 18 sorafenib and analogues were investigated by ESI-IT-MS n and ESI-Q-TOF-MS/MS in the positive ion mode combining with density functional theory (DFT). The positional isomers of sorafenib intermediates and impurities were also distinguished by the relative abundance of characteristic fragment ions and the energy-resolved breakdown curves.…”