Potential antitumor agents. 35. Quantitative relationships between antitumor (L1210) potency and DNA binding for 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) analogs

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Abstract
Factors influencing dose potency of 4''-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) analogs in L1210 [mouse leukemia] assays were investigated by multiple regression analysis. The dependent variable was D40, the dose to provide 40% life extension in L1210 tests. Independent variables examined were chromatographic Rm values, as a measure of agent lipophilic-hydrophilic balance; Rm2; log K, where K is the agent-DNA association constant for poly[d(A-T)]; log T1/2, the half-life for congener thiolytic cleavage; and agent pKa values. A regression equation containing terms in Rm and log K was derived with the latter term accepting the greater proportion of the biological variance. DNA binding of acridine substituted m-AMSA variants is the most important factor influencing dose potency. Modeling of log K for 3-substituted derivatives provided an equation in substituent R constants and molar refractivities (MR).