IRREVERSIBLE ENZYME INHIBITORS . 140 . ACTIVE-SITE-DIRECTED IRREVERSIBLE INHIBITORS DERIVED FROM 1-(3-CHLOROPHENYL)-4,6-DIAMINO-1,2-DIHYDRO-2,2-DIMETHYL-S-TRIAZINE

4,6-Diamino-1,2-dihydro-2,2-dimethyl-1-phenyl-s-triazines bearing the following substituents on the para position were not irreversible inhibitors of dihvdrofolic reductase from L1210 mouse leukemia: OCH2CONH-C6H4SO2F-p (2a), O(CH2)2OC6H4SO2F-p (3a), O(CH2)3OC6H4SO2F-p (7), (CH2)2C6H4SO2F-p (11), and OCH2-CONHC6H4SO2F-m (16). These results contrast with the (CH2)2CONHC6H4SO2F-p derivative (1a) which is an active-site-directed irreversible inhibitor of L1210 dihydrofolic reductase, the difference being rationalized by the difference in allowable ground-state conformations. By limiting the number of ground-state conformations of 2a, 3a, 7, 11, and 16 by insertion of a chloro atom on the meta position of the 1-phenyl-s-triazine moiety, the resultant compounds (2b, 3b, 8, 12, and 15, respectively) were converted into irreversible inhibitors of the enzyme. of these five irreversible inhibitors, 8 and 3b could also inactivate the enzyme from mouse liver; since 2b, 12, and 15 did not inactivate the mouse liver enzyme appreciably, these three compounds showed the desired specificity pattern needed for chemotherapy. © 1969, American Chemical Society. All rights reserved.