Potential antitumor agents. 27. Quantitative structure-antileukemic (L1210) activity relationships for the .omega.[4-(9-acridinylamino)phenyl]alkanoic acids

Publisher Website
Google Scholar
Abstract
Simple carboxylic acid derivatives of 9-anilinoacridine provided high experimental antileukemic (mouse, L1210) activity. The homologous 1''-(CH2)nCOOH congeners also proved active, and there was 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] provided a similar parabolic relationship, which had 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 could be treated as 1 group and a correlation equation derived that was identical with that for the carboxamide variants alone. The optimum Rm value for this group was 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 acted 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 differed in analogues containing the carboxylic acid or alkanesulfonanilide side chains, supporting the view that different site-binding orientations may be involved with these 2 drug classes.