Molecular Pharmacology, Vol 20, 649-656, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

A Comparison of the Inhibition of Bovine and Murine Leukemia Dihydrofolate Reductase by 4,6-Diamino-1,2-dihydro-2,2-dimethyl-1-(3-X-phenyl)-s-Triazines

¹ Department of Chemistry, Pomona College, Claremont, California 91711, and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510

A comparison has been made of the inhibition of two mammalian dihydrofolate reductases, one from bovine liver and the other from a murine tumor (L5178 YR-C₃), by 40 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-X-phenyl)-s-triazines. The K_i values obtained were used to formulate quantitative structure-activity relationships. The 3-X substituents were found to bind in a hydrophobic pocket of the enzyme. Binding was well correlated by the hydrophobic parameter up to ₀ of 1.6-1.7. Distinct differences were found in the inhibition constants for the two different enzymes. However, only one substituent not large enough to extend beyond the hydrophobic pocket showed selectivity. Those substituents, whose values were 1.66, showed no selectivity. These results confirm the hypothesis of Baker [Design of Active-Site-Directed Irreversible Enzyme Inhibitors. Wiley, New York (1967)] that one should not search for selective inhibitors by making variations on that part of a parent molecule binding in hydrophobic space.

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ACKNOWLEDGMENT We wish to thank P. Y. C. Jow for determining the partition coefficients for this paper.