In vivo formation of diazepam-like 1,4-benzodiazepines byPenicillium verrucosum var.verrucosum after administration of 2-aminobenzophenones and glycine

Summary

The in vivo formation of the diazepam-like 1,4-benzodiazepine deschloronordiazepam from its assumed biogenetic precursors, 2-aminobenzophenone and glycine, by the mould strainPenicillium verrucosum var.verrucosum, is described. Deschloronordiazepam formation was established by GC/MSD analysis monitoring characteristic fragment patterns of the benzodiazepine moiety. The identification of deschloronordiazepam was confirmed by feeding experiments of D₅-2-aminobenzophenone, as well as its brominated and chlorinated derivatives to the mould. The formation of the 1,4-benzodiazepine was observed to depend on various factors, e.g. the time of application of the precursors, duration of the incubation and kind of cultivation. The results represent the first actual de novo synthesis of such diazepam-like 1,4-benzodiazepines from plausible biosynthetic precursors in a living organism, in agreement with a biosynthetic concept recently established in our group. Such pharmacologically active 1,4-benzodiazepines had been detected in trace amounts in mammalian and plant tissues. Because of their unususal molecular framework, they had previously been considered not to fit into any conventional biosynthetic route.