THIONO COMPOUNDS. 8. MUTAGENIC ACTIVITY OF REPRESENTATIVE AMIDES OF THIOPHOSPHORIC ACID

Abstract

Amides of thiophosphoric acid were studied, in order to initiate correlations of mutagenicity with structure, by use of a modified Ames assay. Representative thiophosphoramides of the structure (XArNH)₃PS were not mutagenic, irrespective of whether X was a reference hydrogen atom, an electron-withdrawing, or an electron-donating group. One phosphoramidothioate of the structure (2,4-X₂ArNH)P(S)(OCH₂CH₃)₂ effected base-pair mutation when X was F (but not when X was CH₃), when S-9 liver homogenate with exogenous NADP was used; when X was H, only inconsistent mutagenic activity following metabolic activation was observed even at concentrations near those that produced acute cellular toxicity. Mutagenicity of these N-arylamides thus appears to follow guidelines concluded for esters, (RO)₃PS, i.e. that mutagenesis is most probable when two groups are small enough to permit nucleophilic attack by a biomacromolecule on the electrophilic phosphorus atom. That the third group should be electron withdrawing again seems important although it need not be a good leaving group. An alkyl thionamide, [(CH₃)₂N]₃PS, resembled the oxygen counterpart, [(CH₃)₂N]₃PO, to which it probably is biotransformed, in being only marginally mutagenic. We conclude that the hazard of mutagenesis is likely to be less with amides than with esters of thiophosphoric acid and that most of the representative thioamides tested are unlikely to pose serious mutagenic hazards.

Key Words:

• Ames assay
• base-pair mutation
• mutagenesis
• phosphoramidothioate
• thionamide
• thiophosphoramide