IRREVERSIBLE ENZYME INHIBITORS . 137 . ACTIVE-SITE-DIRECTED IRREVERSIBLE INHIBITORS OF DIHYDROFOLIC REDUCTASE DERIVED FROM 6-(P-AMINOMETHYLPHENOXYMETHYL)-2,4-DIAMINO-5-(3,4-DICHLOROPHENYL)PYRIMIDINE BEARING A TERMINAL SULFONYL FLUORIDE

The m-fluorosulfonylbenzoyl derivative (1) of the title compound was previously shown to be an active-sitedirected irreversible inhibitor of the dihydrofolic reductase from the L1210/FR8, L1210/DF8, and L1210/0 strains of mouse leukemia at a concentration of 10-7 M; good specificity was seen since 1 at 10-6 M failed to inactivate the enzyme from mouse liver. Since 1 showed good specificity, but probably required too high a concentration io be useful in vivo, 13 analogs were synthesized where the benzoyl moiety was varied to determine if more potent compounds with a similar specificity could be found. Some of the variants showed more potency such as the p-fluorosulfonylbenzoyl (2) and the 4-chloro-3-fluorosulfonylbenz.oyl (4) derivatives, but specificity was lost, since the dihydrofolic reductase from mouse liver could also be inactivated by 2 or 4. © 1969, American Chemical Society. All rights reserved.