Tandem mass spectrum of a growth hormone secretagogue: amide bond cleavage and resultant gas-phase rearrangement.
Compound 1 [N-[1(R)-[(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 MSn 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.
Qin
Xue-Zhi
XZ
Pharmaceutical Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. zuezhi_qin@merck.com
D000577:Amides / Q000737:chemistry*; D013006:Growth Hormone / Q000378:metabolism*; D007211:Indoles; D009682:Magnetic Resonance Spectroscopy; D010880:Piperidines; D011522:Protons; D021241:Spectrometry, Mass, Electrospray Ionization
D000577:Amides; D007211:Indoles; C452780:MW 528; D010880:Piperidines; D011522:Protons; D013006:Growth Hormone