IRREVERSIBLE ENZYME INHIBITORS . 141 . ACTIVE-SITE-DIRECTED IRREVERSIBLE INHIBITORS OF DIHYDROFOLIC REDUCTASE DERIVED FROM 1-(P-(P-FLUOROSULFONYLPHENYLUREIDOMETHYL)-PHENYL)-4,6-DIAMINO-1,2-DIHYDRO-2,2DIMETHYL-S-TRIAZINE

The title compound (1) showed a poor order of active-site-directed irreversible inhibition of dihydrofolic reductase from mouse L1210 leukemia, liver, spleen, or intestine since too high a concentration of inhibitor had to be used to show good inactivation. Substitution of a methyl group meta to the SO2F moiety of 1 gave compound 6 that was still a relatively poor irreversible inhibitor of the L1210 enzyme, but now showed tissue specificity by its failure to inactivate the liver enzyme. More effective irreversible inhibitors (5, 8, 9) were obtained by substitution of a chloro atom meta to the junction of the 1-phenyl to the s-triazine ring; however, these compounds did not show specificity since the liver enzyme was still inactivated. © 1969, American Chemical Society. All rights reserved.