Electrospray mass spectrometry of angiotensin-converting enzyme inhibitors

Abstract

Electrospray ionisation (ESI) mass spectrometry combined with collision-induced decomposition of ions given by captopril, lisinopril and enalaprilat, angiotensin-converting enzyme (ACE) inhibitors, has been used to characterise these compounds. As expected, the ESI mass spectra are characterised by the presence of abundant [M H] ions with very little fragmentation at low cone voltages. Fragment ions are produced by collision-induced decomposition of these ions at higher cone voltages, and in MS/MS experiments. Fragmentation pathways and structures of fragment ions observed have been proposed. # 1998 John Wiley & Sons, Ltd. Received 26 August 1998; Revised 29 September 1998; Accepted 4 October 1998 Captopril, lisinopril and enalaprilat, angiotensin-converting enzyme (ACE) inhibitors, have been used as therapeutic agents because, in addition to their specific enzyme inhibition, they possess anti-inflamatory properties and protect the ischemic myocardium against reperfusion injury. These various actions of ACE inhibitors may be related to their ability to scavenge deleterious free radicals [1][2][3][4] . It has been shown that captopril, lisinopril and enalaprilat ACE inhibitors are effective OH . radical scavengers. 4 This was established by the deoxyribose assay in the presence of iron complexed with EDTA.5 ACE inhibitors also prevent deoxyribose degradation, in reaction mixtures which do not contain EDTA, suggesting that they exhibit some degree of metal-binding capabilities. 6,7 Furthermore, evidence of the formation of complexes between ions of metals, copper in particular, and ACE inhibitors, especially captopril and lisinopril, has recently been reported. 8 Because of the importance of these inhibitors, we have undertaken a study of their electrospray ionisation (ESI) mass spectra and their low energy MS/MS spectra with a view to establishing a simple method of characterising these compounds. EXPERIMENTAL Instrumentation and proceduresThe experiments were performed using a "Quattro II" QhQ tandem mass spectrometer (Micromass, Altrincham, UK) equipped with an atmospheric pressure ionisation source operated in the nebuliser-assisted electrospray mode. The potential of the electrospray needle was set at 3.5 kV and the extraction cone voltage was varied between À30 and À60 V and was optimised for each MS/MS spectrum. The source temperature was held at 70°C and samples were introduced into the mass spectrometer by means of a fused silica capillary tube and a Harvard syringe pump. Mass spectra were acquired over the range m/z 100-1000 during 10 s scans, operating the data system in the multichannel acquisition (MCA) mode. Calibration was performed using NaI.For low energy collision-induced decomposition (CID) experiments, preliminary work was carried out in conventional MS mode on the [M H] ions at higher cone extraction voltages. More detailed information was obtained, using MS/MS, by selecting the precursor ion in the first quadrupole mass analyser, Q1, subjecting this to CID in the hexapole collision cell...

Mass spectral fragmentation reactions of angiotensin-converting enzyme (ACE) inhibitors

“…This mechanism depends neither on the initial location of the ionizing proton nor its mobility, in this case from a more basic functional group to a less basic functional group. An interesting aspect of the mechanism summarized in Scheme 1 (culminating in Structure B) is the transfer/rearrangement of the carboxylic acid group (i.e., electrophilic attack of a carboxylic acid carbonyl carbon on the lone pair electrons of a secondary nitro- The mechanism leading to Structure A was proposed in a previous study [19].…”

“…Such rearrangement processes are of interest from the perspective of fundamental gas-phase ion chemistry, as well as for the impact they have on the interpretation of collision-induced dissociation spectra in the context of characterization of unknown organic compounds. Florêncio and coworkers [19] reported the fragmentation behavior of lisinopril, 1, under low-energy collisioninduced dissociation conditions. Among the dissociation reactions exhibited by the [M ϩ H] ϩ ion (m/z 406) of lisinopril (Figure 2), elimination of neutral C 5 H 7 NO (m/z 309) was particularly interesting since it requires that a functional group migration/rearrangement must either precede or accompany the elimination of dihy- dropyrrole and carbon monoxide.…”

“…Two publications have detailed the interactions of some of these molecules with metal ions, using mass spectrometry and ultraviolet spectroscopy to evaluate their potential role as radical scavengers [17,18]. At least four compounds in this class have been the focus of studies where collision-induced dissociation and tandem mass spectrometry (MS/MS) have been used to probe their dissociation reactions [19,20]. Two of those compounds, lisinopril and zofenapril, exhibited interesting rearrangement reactions in the unimolecular dissociation chemistry of their protonated molecules ([M ϩ H] ϩ ) under conditions of low-energy collisional activation.…”

High‐throughput quantification of perindopril in human plasma by liquid chromatography/tandem mass spectrometry: application to a bioequivalence study

“…[M+H] + was the predominant ion in the Q1 spectrum and was used as the precursor ion to obtain product ion spectra. The low intensity peak at m/z 295 is presumably due to an ion formed by the loss of the ethoxycarbonyl moiety, whereas cleavage ( to the carbonyl group after protonation on the ring N atom13 can give rise to the major fragment ion at m/z 172 (Fig. 2).…”

Characterization of impurities in the bulk drug lisinopril by liquid chromatography/ion trap spectrometry

“…The product ion at m/z 263 corresponded to the dipeptide N-terminal a 1 ion with the combined loss of proline and CO, while ion at m/z 246 was formed from subsequent loss of NH 3 . The product ion at m/z 309 was formed through a rearrangement (Florêncio et al, 1998;Hiserodt et al, 2007), with the elimination of dihydropyrrole and CO, and could be used to characterize the 6-amino-2-(1-carboxy-3-phenylpropyl-amino)-hexanoic acid structure. The product ion at m/z 227 was formed by the neutral loss of 2-amino-4-phenylbutanoic acid (179 Da).…”