Comparison of the in vivo and in vitro antileukemic activity of monosubstituted derivatives of 4'-(9-acridinylamino)methanesulfon-m-anisidide.

The growth-inhibitory activity of 4'-(9-acridinylamino)methanesulfon-m-anisidide and 47 acridine-monosubstituted derivatives has been measured using cultures of L1210 murine leukemia cells grown for 3 days in the presence of each drug. The results have been compared with previously published in vivo antitumor activity and physicochemical properties related to DNA binding, acridine base strength, stability to chemical attack by thiols, and lipophilicity. Multiple-parameter regression equations show that both dose potency and host toxicity in mice are related to a combination of in vitro activity and a nonlinear (quadratic) term in lipophilicity. The in vitro activity can in turn be modeled as a combination of terms representing DNA binding, ability to quench the fluorescence of DNA-bound ethidium stability to thiolysis, and lipophilicity. It is hypothesized that the terms for thiolytic stability and lipophilic-hydrophilic balance describe the availability of the drug to the cell, and that the DNA binding constant determines what proportion of the available drug is bound to DNA, the proposed target site. The remaining terms could reflect changes in the geometry of drug-DNA binding, which in turn affect the intrinsic activity of these drugs when bound at their site of action.