In vivo formation of diazepam-like 1,4-benzodiazepines by Penicillium verrucosum var. verrucosum after administration of 2-aminobenzophenones and glycine.
The in vivo formation of the diazepam-like 1,4-benzodiazepine deschloronordiazepam from its assumed biogenetic precursors, 2-amino-benzophenone and glycine, by the mould strain Penicillium 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 unusual molecular framework, they had previously been considered not to fit into any conventional biosynthetic route.
Bringmann
G
G
Institute of Organic Chemistry, University of Würzburg, Federal Republic of Germany.
Mader
T
T
D014151:Anti-Anxiety Agents / Q000378:metabolism*; D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism*; D001577:Benzophenones / Q000494:pharmacology*; D050260:Carbohydrate Metabolism; D003470:Culture Media; D003975:Diazepam / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D005998:Glycine / Q000494:pharmacology*; D006219:Halogens / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D010407:Penicillium / Q000187:drug effects* / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D001577:Benzophenones; D003470:Culture Media; D006219:Halogens; D001569:Benzodiazepines; D003975:Diazepam; D005998:Glycine