Tandem mass spectrum of a growth hormone secretagogue: Amide bond cleavage and resultant gas-phase rearrangement

Abstract

Compound 1 {N-[1(R) Ϫ [(1,2-dihydro-1-methylsulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide}(MW 528) is an orally-active growth hormone secretagogue (GHS). As part of a continual effort to analyze the ESI/MS and MS n data of novel drugs, the ESI/MS and MS/MS data of protonated 1 (m/z 529) are analyzed and reported here. The analyses reveal that under low-energy collision-induced dissociation (CID) in an ion trap or a quadrupole collision cell, protonated 1 undergoes a gas-phase rearrangement to form protonated 3 (m/z 357) which competes with the y-and b-type product ions during the amide bond cleavages of protonated 1. It is proposed that when the b-type ion is formed by cleavage of the piperidine amide bond, piperidine (a neutral species) and the b-ion (a cation) form an ion-neutral complex. In this complex, piperidine functions as a nucleophile to attack the benzylic carbon of the b-ion, and the protonated ether group in the b-ion acts as a leaving group, which results in the migration of the benzylic group to the piperidine amine to form protonated 3. Protonated 2 (an analog of 1) was studied under the same experimental conditions. The results show that protonated 2 undergoes a similar rearrangement to form protonated 3. While this rearrangement is a relatively minor fragmentation process for protonated 1, it is a predominant process for protonated 2. This phenomenon is explained in terms of the proposed ion-neutral-complex mechanism. (J Am Soc Mass Spectrom 2002, 13, 371-377)

Using tandem mass spectrometry to predict chemical transformations of 2-pyrimidinyloxy-N-arylbenzyl amine derivatives in solution

“…Generation of the K series ions is the most characteristic fragmentation pathway for protonated 2-pyrimidinyloxy-N-arylbenzyl amine derivatives. A benzyl migration reaction with intramolecular S N 2 mechanism was proposed to explain this process [17,26,27]. Since the solvation effect and hydrogen bond effect does not affect gas-phase reactions, the intrinsic nucleophilicity of the tertiary amine of pyrimidine facilitated such S N 2 reaction.…”

Low‐energy collision‐induced dissociation of sildenafil thiono analogues: gas‐phase intramolecular nucleophilic substitution through ion‐neutral complexes between a cationic substrate and a thione‐containing neutral nucleophile

“…Deuterated 1 was prepared by dissolving 0.5 mg of compound 1 in 10 mL D 2 O (0.1% formic acid), as described previously. 4,5 Figures 1(A) and 1(C) show the MS/ MS spectra of sildenafil obtained using the ion trap (cut-off 27% of the m/z value of the precursor ion) and the triple-quadrupole mass spectrometer, respectively. Representative fragment ions of sildenafil were observed at m/z 377, 313, 311, 299, 283, 163, 100 and 99, and this fragmentation has been well described previously.…”

Studies of rearrangement reactions of protonated and lithium cationized 2-pyrimidinyloxy-N-arylbenzylamine derivatives by MALDI-FT-ICR mass spectrometry

“…A thorough understanding of the MS/MS and MS n data of these herbicides is necessary for further development of these compounds [2]. Protonated ions often undergo gas-phase rearrangement [3][4][5][6][7][8][9][10][11][12][13]. The gas-phase rearrangement reactions of peptides and modified peptides have been investigated in many previous reports [3][4][5][6][7][8][9].…”