RELATIONSHIPS BETWEEN STRUCTURE AND KINETICS OF CYCLIZATION OF 2-AMINOARYL AMIDES - POTENTIAL PRODRUGS OF CYCLIZATION-ACTIVATED AROMATIC MUSTARDS

2-Nitroaryl amides of general structure I are proposed as bioreducible prodrugs, capable of releasing cytotoxic aminoaniline mustards V on b ioactivation by spontaneous cyclization of the resulting 2-aminoaryl a mides II via a tetrahedral intermediate, III. This concept allows sepa rate optimization of the substituent effects influencing nitro-group r eduction and mustard reactivity. A series of model 2-aminoaryl amides has been synthesized, and their rates of cyclization have been studied ; these varied by a factor of more than 50 000-fold (k(obs) from 0.000 40 to 21 min(-1)) at pH 2.4. For three compounds studied in detail, th e rates were linearly dependent of pH, indicating that no change in th e mechanism of the rate-determining step occurs over the pH range stud ied. The nucleophilicity of the amino group had a modest influence on the kinetics of cyclization, with electron-withdrawing groups slowing the rate. The geometry of the compound was also important, with struct ure-activity relationships indicating that the rate of cyclization is greatly enhanced by the preorganization of the molecule. In contrast, 4-substitution on the leaving aniline by a variety of groups had littl e effect on the cyclization reaction. These results are consistent wit h the rate-determining step being formation of the tetrahedral interme diate. These model studies suggest that the phenyldimethylacetamide sy stem could be developed as a prodrug system for the bioreductively-tri ggered release of amines. Further substantial rate enhancements appear possible by alterations in the geometry of the system, whereas substi tution of electron-withdrawing groups (required to raise the nitro-gro up reduction potential into the appropriate range) has only relatively modest retardation effects on rates of cyclization. More rigid system s may also be useful; a nitronaphthaleneacetamide analogue cyclized sp ontaneously during nitro-group reduction, suggesting a very short half -life for the reduced intermediate (amine or hydroxylamine).