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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.

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 Ki 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 π up to π 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 π 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.

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