Potential antitumor agents. 35. Quantitative relationships between antitumor (L1210) potency and DNA binding for 4'-(9-acridinylamino)methanesulfon-m-anisidide analogues.
Factors influencing dose potency of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) analogues in L1210 assays have been 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 Rm2 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).
D000609:Aminoacridines / Q000378:metabolism / Q000494:pharmacology*; D000677:Amsacrine; D000818:Animals; D000970:Antineoplastic Agents; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000378:metabolism*; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D013329:Structure-Activity Relationship
D000609:Aminoacridines; D000970:Antineoplastic Agents; D000677:Amsacrine; D004247:DNA