Synthesis and mutagenicity of a series of nitrated carbazoles and hydroxycarbazoles.

Nitrated derivatives of the aza-arenes carbazole and 2-hydroxycarbazole were synthesized and tested for mutagenicity in the Ames plate-incorporation assay. 3,6-Dinitrocarbazole was the most mutagenic towards Salmonella typhimurium strain TA98 (> 100 revertants/micrograms, 25 revertants/nmol, with or without S9) followed by 2-hydroxy-1,3,6-trinitrocarbazole (24 revertants/micrograms, 7 revertants/nmol without S9) and 2-hydroxy-3-nitrocarbazole (27 revertants/micrograms, 6 revertants/nmol without S9). 2-Hydroxy-1,3-dinitrocarbazole, 1,6-dinitrocarbazole, 3-nitrocarbazole and 1-nitrocarbazole ranged from moderately to weakly active (7-1 revertants/micrograms, 2-0.3 revertants/nmol without S9). Carbazole and 2-hydroxycarbazole, and 2-hydroxy-1-nitrocarbazole, were quite inactive. Activity was generally decreased by the presence of S9, except for the dinitrocarbazoles, and was also lower in the variant TA98NR, indicating that mutagenicity was largely dependent on the presence of the 'classical' bacterial nitroreductase. The relative activities of these compounds are consistent with the hypothesis that structural features (orientation of the nitro group relative to the plane and to the long axis of the molecule, and ability to resonance-stabilize the positive charge on the arylnitrenium active electrophile intermediate) are major influences determining mutagenic potency of nitrated compounds.