An unusual rearrangement of Zofenopril, a new ACE inhibitor drug: mass spectrometric and conformational studies

• Published in: Journal of mass spectrometry Vol. 37; no. 12; pp. 1258 - 1265
• Main Authors: Cartoni, Antonella, Altamura, Maria, Animati, Fabio, Balacco, Giuseppe, Cosi, Riccardo, Ettorre, Alessandro, Madami, Andrea, Triolo, Antonio
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.12.2002; Wiley
• Subjects: ACE inhibitor; Angiotensin-Converting Enzyme Inhibitors - chemistry; Antihypertensive agents; Biochemical Research Methods; Biochemistry & Molecular Biology; Biological and medical sciences; Captopril - analogs & derivatives; Captopril - chemistry; Cardiovascular system; Chemistry; Chemistry, Analytical; electrospray ionization mass spectrometry; Life Sciences & Biomedicine; Mass Spectrometry; Medical sciences; Molecular Structure; Pharmaceutical Preparations - chemistry; Pharmacology. Drug treatments; Physical Sciences; rearrangement; Science & Technology; Spectroscopy; tandem mass spectrometry; Technology; Zofenopril; electrospray ionization mass spectrometry; tandem mass spectrometry; IONS; Zofenopril; FRAGMENTATION; SPECTRA; ACE inhibitor; rearrangement; PEPTIDE; Chemical rearrangement; Collisional activation; Enzyme; Enzyme inhibitor; Fragmentation pattern; Electrospray; Organic sulfide; Peptidases; α-Aminoacid; Peptidyl-dipeptidase A; Thioester; Mass spectrometry MS/MS; Hydrolases; Peptidyl-dipeptidases; Antihypertensive agent; Conformation
• ISSN: 1076-5174; 1096-9888
• DOI: 10.1002/jms.392

Zofenopril (1) is a new ACE inhibitor, used in therapy for hypertension and post‐myocardial infarction. The protonated quasi‐molecular ion (m/z 430) of 1, obtained under positive electrospray ionization conditions, loses a benzoic acid molecule (m/z 308), which in turn decomposes via loss of CO (m/z 280) when low‐energy collisional‐induced dissociation (CID) and in‐source experiments are performed. This rearrangement is the main fragmentation process and can be observed both in‐source and in the product ion tandem mass spectra, using either an ion trap or a triple quadrupole instrument. Other known diastereoisomers of 1, an impurity with an acetyl in the place of the benzoyl group (2) and an impurity with two propanoyl chains in series (3), give the same rearrangement. On the other hand, the mass spectra of the methyl ester (4) and an impurity with two proline moieties (5) do not show this unusual fragmentation. Time‐resolved CID spectra of 1 show that the rearrangement occurs after about 2 ms, a time scale comparable to those of the other non‐rearrangement cleavages. These experiments suggest a conformation in the gas phase for 1 in which the benzoyl group is close to the hydroxyl of the carboxylic acid group, from which the rearrangement could readily occur. Since compounds 4 and 5 do not show the same behaviour, the presence of a carboxylic acid in the proline ring seems to play a crucial role in the rearrangement, probably due to an intramolecular hydrogen bond. To confirm this hypothesis, deuterium exchanges in mass spectrometric experiments and a conformational analysis via computational methods were performed. Copyright © 2002 John Wiley & Sons, Ltd.