Identification of Gut Microbial Metabolites of a Synthetic Nitric Oxide-Releasing Farnesylthiosalicylic Acid Derivative, an Antitumor Agent

Abstract

3-(phenylsulfonyl)- 4-(4-((S)-1-(2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio) benzoyl) pyrrolidine-2-carbonyloxy)but-2-ynyloxy)-1,2,5-oxadiazole-2-oxide is a novel furoxan-based nitric oxide-releasing derivative of arnesylthiosalicylic acid. Previous experimental results showed that it was a good prospective anticancer agent both in vitro and in vivo. To study its route of administration, mechanism of action, and metabolic processes, the metabolites of this derivative were studied in an in vitro fermentation model with rat intestinal microflora. A high performance liquid chromatography–electrospray ionization tandem mass spectrometry method in positive ion mode was used to elucidate the structures of these metabolites. By comparing changes in the pseudomolecular ions, fragmental ions, and retention times with those of parent drug, four metabolites were observed, which were associated with the following metabolic events: reduction of the aliphatic triple bond, hydroxylation of the benzene ring, loss of NO free radical, and hydrolysis of the ester bond.