Potential antitumor agents. 33. Quantitative structure--activity relationships for mutagenic activity and antitumor activity of substituted 4'-(9-acridinylamino)methanesulfonanilide derivatives.

Abstract

A series of substituted 4'-(9-acridinylamino)methanesulfonanilide (AMSA) derivatives have been tested for mutagenicity using Salmonella typhimurium strain TA 1537 and for antitumor activity against the L1210 leukemia in mice. Two measures of mutagenic activity were determined and quantitative structure--activity relationships (QSAR) developed for them. M50, the percentage of drug-induced mutant colonies observed at the concentration providing 50% inhibition of bacterial growth, is a measure of mutagenic efficiency. The lowest molar drug concentration (1/C) needed to induce a fixed proportion of revertants (chosen as 50 per 10(8) bacteria) is a measure of mutagenic effectiveness. The two measures of antitumor activity modeled were ILSmax (the percent increase in life span observed for each derivative at its LD10 dose), a measure of tumor cell selectivity, and 1/D40 (the dose of drug to provide an ILS of 40%), a measure of dose potency. These measures of bioactivity were intercompared and modeled in terms of a number of drug physicochemical properties. The results show that drug lipophilic/hydrophilic balance is the dominant factor in determining both mutagenic and antitumor activity, although other factors are involved. The two different types of activity can be readily separated in the AMSA drug series by appropriate choice of substituent and adjustment of overall drug lipophilic/hydrophilic balance.