Potential anticancer agents. XVII. New developments in the benzoic acid nitrogen mustards area

In order to obtain aromatic nitrogen mustards with improved therapeutic index against experimental neoplasms, greater than 75 new compounds were synthetized and studied. Their structure-activity relationship analysis led to the following conclusions: (a) the carboxylic group (especially when located in the meta position with respect to the nitrogen mustard group) exerts a favorable effect on the biologic properties of such compounds, probably by improving their transport characteristics; (b) a linear relationship was found between the chemical reactivity (expressed as alkylation rate, log k66) and toxicity (LD50) of 31 investigated compounds; and (c) the ortho effects also seem to be of importance in this area for a more accurate control of the nitrogen mustard activity. Other criteria (ie, log P, nucleophilicity of the target centers) involved in the rational design of aromatic nitrogen mustards are discussed. The design of new derivatives was oriented toward compounds which (a) were able to couple with selected proteins (ie, antibodies) leaving the cytotoxic moiety intact, and (b) were obtained by coupling of the 3-N,N-bis(2-chloroethyl)amino-4-methyl-benzoyl moiety with selected carriers (steroids, chromanones, etc) by way of an esteric bond.