Structure-antileukemic activity relationship study of B- and D-ring modified and nonmodified steroidal esters of 4-methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid: a comparative study

This study was designed as a rational continuation of our research regarding the functional requirements essential for the antileukemic activity of compounds comprising an alkylating moiety and a modified steroid. The steroidal esteric derivatives of 4-methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid were tested on leukemias P388 and L1210 in vivo and in normal human lymphocytes in vitro. Among them the B-lactamic steroidal esters proved more potent antileukemic agents than the 7-oxidized and those with a simple B-ring, but not more effective inducers of DNA damage and cell cycle arrest in vitro. We speculate that these results indicate a different mechanism of action induced by the lactamized B steroidal ring, in comparison to the 7-keto or the D-lactamic groups, which involves the interaction of the -NHCO- moiety with cellularcomponents essential for tumor growth. 4-Methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid proved a more proper module for the B-lactams than chlorambucil and phenyl acetic acid's nitrogen mustard probably because the esteric bond is less cleaved by the esterases, resulting in an increased concentration of the drug in the vinicity of the target site essential for an antineoplasmatic response.