Quantitative correlations of biological activities of dactinomycin analogs and methotrexate derivatives with van der Waals volume.

The biological activities namely the ability to bind with DNA base pairs and the in vitro inhibition of human lymphoblastic leukemia cells of certain C-7- and N2-substituted dactinomycin (actinomycin D, AMD) analogs, and the growth inhibitory activity of a series of side chain substituted methotrexate (MTX) derivatives against L 1210 mouse leukemia cells in culture and their binding affinity for dihydrofolate reductase (DHFR) enzyme extracted from this system and L. casei are found to be significantly correlated with van der Waals volume of the substituents. In case of MTX derivatives, not only the side chain substituted analogs but certain ring substituted analogs, too, are shown to have their different activities dependent upon the Vw of the substituents. In case of side chain substituted analogs, however, it is found that the size of the substituent of alpha-position produces a greater effect on the activity than that of gamma-position. Based on the correlating equations obtained it is assumed that in these cases the drug-receptor interaction might be involving either hydrophobic interaction or the van der Waals type of interaction.