Synthesis and Evaluation of Esters of N,N-Bis(2-chloroethyl)-p-aminophenol and N,N-Bis(2-bromoethyl)-p-aminophenol as Potential Antitumor Agents

A series of benzoate esters of N,N-bis(2-chloro-(or bromo-)ethyl)-p-aminophenol have been synthesized and evaluated as antitumor agents against the Walker 256 carcinosarcoma to further test the hypothesis that hydrolysis of the ester linkage may be a prerequisite for antitumor activity. The 2,6-dimethylbenzoate of 4-(N,Ndiethylamino (phenol was not hydrolyzed by crude rat liver esterases, and the toxicities and antitumor activities of the corresponding mustards were much reduced relative to the parent unsubstituted benzoate. These results lend some support to the previously expressed hypothesis that hydrolysis to the free phenolic mustards is a necessary step for antitumor activity. In a series of meta- and para-substituted benzoates of 4-(N,N-diethylamino (phenol, hydrolysis by the rat liver esterase preparation was dependent upon the electronic effects of the substituents but this dependence did not extend to the toxicities or antitumor activities of the corresponding nitrogen mustards.