Identification of the principal circulating metabolite of a synthetic 5,4′-diaminoflavone (NSC 686288), an antitumor agent, in the rat |
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Authors: | Lawrence R. Phillips Chris Bramhall John Buckley Tracy Wolfe Tyra L. House Sherman F. Stinson |
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Affiliation: | a Laboratory of Drug Discovery, Research and Development, Developmental Therapeutics Program, Division of Cancer Treatment, Diagnosis and Centers, National Cancer Institute, Frederick, MD 21701, USA;b SAIC-Frederick, Frederick Cancer Research and Development Center, Frederick, MD 21701, USA |
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Abstract: | During the course of our study to develop analytical methodology for quantitating the investigative antitumor agent 5-amino-2-(4-amino-3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one (DAF; NSC 686288) in plasma, a significant concentration of a metabolite was observed in a post-dosed rat. The results of electron-ionization (EI) mass spectrometric analysis of the metabolite suggested that N-acetylation had occurred, but, interestingly, that only one of the compound’s two primary amino groups had been transformed. Comparing the mass spectra and gas chromatographic retention times of a mono-acetylated sample of DAF and that of the metabolite showed both to be the same. A retro-Diels–Alder (RDA) fragmentation of the B ring of DAF results in formation of two abundant product ions, each retaining one of the amino groups. The EI mass spectrum of mono-N-acetamido-d3 DAF shows loss of ketene-d2, leading to formation of an –NHD group. The ensuing RDA fragmentation easily identifies which of the two product ions contains the deuterium, thereby allowing us to assign the site of N-acetylation as the amino group on ring C (the 4′ position) of DAF. |
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Keywords: | 5,4′ -Diaminoflavone NSC 686288 |
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