Structure-activity relationships of the azide metabolite, azidoalanine, in S. typhimurium

Azide is metabolized to the proximate mutagen, L-azidoalanine in bacterial systems. While this novel mutagenic metabolite plays a key role in azide mutagenesis, the biochemistry of this role is unknown. The chemical synthesis of authentic racemic azidoalanine and several derivatives thereof allowed the exploration of structure-activity relationships with this unique mutagen. We found that whereas azide, azidoalanine and azidoalanine tert.-butyl ester were of comparable mutagenic potency, derivatives which lack the free amino group, such as azidopropionic acid and amino-blocked azidoalanine, were orders of magnitude less active. These findings demonstrate that the free amino group is essential for significant activity, while the carboxyl group may be less important. This conclusion together with the finding that DL-azidoalanine is a less potent mutagen than azide itself, suggests that the metabolite, while necessary for azide mutagenicity, may not be the ultimate mutagenic species. Instead, the data are consistent with the hypothesis that azidoalanine requires further bioactivation.