Tandem mass spectrum of a farnesyl transferase inhibitor--gas-phase rearrangements involving imidazole.
Compound 1 (1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)imidazolylmethyl]-2-piperazinone hydrochloride) is a farnesyl transferase inhibitor intended for treatment of cancer. A detailed analysis of the electrospray ionization mass spectrometry and tandem mass spectrometry data of protonated 1 shows that in the gas phase, upon collision-induced dissociation, this ion undergoes complicated rearrangement and fragmentation. These processes include a novel two-step rearrangement. The first step involves a gas-phase intramolecular S(N)2 reaction that forms an intermediate. The second step consists of three competitive rearrangement/fragmentation pathways of the intermediate, giving rise to protonated 2, protonated methylene-imidazole, and a distonic methylimidazole radical cation. Deuterated 1 was studied under the same experimental conditions, and the results strongly support the proposed two-step rearrangement process. It is noted that the unique structure of 1, especially the imidazole ring of 1, plays a critical role in the rearrangement of protonated 1.
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WP78-302, Merck Research Laboratories, West Point, PA 19486, USA.
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D051231:Farnesyltranstransferase; D007093:Imidazoles / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods
C439809:1-(3-chlorophenyl)-4-(1-(4-cyanobenzyl)imidazolylmethyl)-2-piperazinone; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010879:Piperazines; C029899:imidazole; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase