ABSTRACT
Alpha-Terthienyl (1) is a trithiophene found widely distributed in plants. Other naturally occurring trithiophenes are less widely distributed, but nonetheless exhibit potent antiviral and cytotoxic activities. A synthetic analog of 1, 2,5-bis(5-hydroxymethyl-2-thienyl)furan (2; NSC 652287) has recently been shown to possess exceptional activity and selectivity against several cell lines of the National Cancer Institute (NCI) anticancer drug screen. When incubated with the S9 subcellular fraction of dog liver cells, the concentration of 2 was observed to decline as a function of time, with a concomitant increase in a significant, time-dependent concentration of an unknown entity. The results of electron-ionization mass spectrometric analysis of the metabolite indicate an increase in 14 amu over that of 2, leading to suspicions that either an oxidation or a methylation had occurred. Results of differential derivatization and accurate mass analysis allow us to propose that metabolism of 2 involves the biotransformation of one of the two hydroxymethyl groups of 2 into a carboxylic acid functionality. This is further supported by separate experiments involving chemical oxidation and S9 incubation of 5-[5-[5-hydroxymethyl-2-thienyl]-2-furanyl]-2-thiophenecarboxaldehyde: comparing the mass spectra and gas chromatographic retention times of the resulting products to those of the identified metabolite of 2 show all to be the same.
