Diazepam Pathway Map

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This pathway was contributed by Lynda Ellis and Michael Turnbull, University of Minnesota.

Diazepam, 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one, is a widely used drug. It is used as an anticonvulsant, sedative, and muscle relaxant, and has a long duration of action (PubChem, 2011).

The fungus Aspergillus niger J/8 N-demethylates diazepam to form 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-one. This demethylation step may be carried out by a transmethylase, hydrolytic demethylase or one of several different types of oxidative demethylases, so the generic "A" is used. The diazepin ring in the demethylated compound is then cleaved. It transiently forms 2-amino-N-(2-benzoyl-4-chlorophenyl)acetamide, which is N-acetylated to form N-(2-benzoyl-4-chlorophenyl)-2-acetamidoacetamide. The fungus Penicillium velutinum cleaves the diazepin ring at the same position without prior N-demethylation and performs the same N-acetylation, to form N-(2-benzoyl-4-chlorophenyl-2-acetamido-N-methylacetamide. Other fungi can demethylate diazepam, but this is the first report of fungal diazepam ring cleavage (Ambrus et al. 1975).

A mixed microbial culture from activated sludge treatment has also been shown to demethylate diazepam to form 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-one (Helbling et al., 2010). The same culture also formed a mono-hydroxylated diazepam derivative, but the exact position of the hydroxyl group was not further specified.

The following is a text-format diazepam pathway map. An organism which can initiate the pathway is given, but other organisms may also carry out later steps. Follow the links for more information on compounds or reactions. This map is also available in graphic (10k) format.

 

                  Diazepam                           Diazepam       
           Aspergillus niger J/8              Penicillium velutinum 
                     |                                  |
                     |                                  |
                     | A                                | diazepam
                     |                                  | cyclohydrolase 
                     |                                  | 
                     v                                  v 
             7-Chloro-5-phenyl-              [2-Amino-N-(2-benzoyl-]
         3H-1,4-benzodiazepin-2-one     [4-chlorophenyl)-N-methylacetamide]
                     |                                  |
                     | 7-chloro-5-phenyl-3H-            | 2-amino-N-(2-benzoyl-
                     | 1,4-benzodiazepin-2-one          | 4-chlorophenyl)-N-methylacetamide
                     | cyclohydrolase                   | N-acetylase
                     |                                  |
                     v                                  v
         [2-Amino-N-(2-benzoyl-]           N-(2-benzoyl-4-chlorophenyl-
        [4-chlorophenyl)acetamide]        2-acetoamido-N-methylacetamide
                     |
                     | 2-amino-N-(2-benzoyl-
                     | 4-chlorophenyl)acetamide
                     | N-acetylase
                     |
                     v
       N-(2-benzoyl-4-chlorophenyl)-
            2-acetamidoacetamide

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Page Author(s): Lynda Ellis and Michael Turnbull

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