Potential antitumor agents. 27. Quantitative structure--antileukemic (L1210) activity relationships for the...

Simple carboxylic acid derivatives of 9-anilinoacridine (e.g., 1,R=-COOH) provide high experimental antileukemic (L1210) activity. The homologous 1'-(CH2)nCOOH congeners also prove active, and there is a parabolic interrelationship between maximum increase in life span in L1210 tests and Rm values used as a measure of agent lipophilic--hydrophilic balance. The corresponding carboxamides [1'-(CH2)nCONH2] provide a similar parabolic relationship, which has an optimum Rm value displaced from that of the acids. Earlier examined 1'-NHSO2(CH2)nCH3 variants, the 3-NHCOCH3 congeners of these, and the carboxamide [1'-(CH2)nCONH2] and sulfonamide [1'-(CH2)nSO2NH2] homologues can be treated as one group and a correlation equation derived that is identical with that for the carboxamide variants alone. The optimum Rm value for this group is displaced from that of the acids by the equivalent of 1.8 log P units on the octanol--water scale. In this drug series a carboxylic acid residue acts as an acceptable hydrophilic unit, providing a log P contribution intermediate between that of the un-ionized acid and the totally ionized carboxylate anion. Quantitative effects of acridine ring substituents on L1210 activity differ in analogues containing either carboxylic acid or alkanesulfonanilde side chains, supporting the view that different site-binding orientations may be involved with these two drug classes.