IRREVERSIBLE ENZYME INHIBITORS . 0142 . FURTHER STUDIES ON ACTIVE-SITE-DIRECTED IRREVERSIBLE INHIBITORS OF DIHYDROFOLIC REDUCTASE DERIVED FROM 5-(P-AMINOPHENOXYPROPYL)-2,4,6-TRIAMINOPYRIMIDINE BEARING A TERMINAL SULFONYL FLUORIDE

5-[p-(m-Fluorosulfonylbenzamido)phenoxypropyl]-2,4,6-triaminopyrimidine (1) at a Ki coneeiitration is an active-site-direeted irreversible inhibitor of the dihydrofolic reductase from three strains of L1210 mouse leukemia: furthermore, 1 at 40Ki concentration showed no irreversible inhibition of enzyme from mouse liver. The lack of effective in vivo action of 1 has been attributed to its relatively high Ki ≃ 1 μM. The maximum enhancement in reversible binding that could be achieved by substitution of chloro, methyl, or isopropyl on one of the two benzene rings was only about twofold, as seen with the 2-chlorophenoxy analog (9) of 1: this was still insufficient for effective in vivo activity. The specificity patterns of irreversible inhibition with the four analogs of 1 are presented and discussed. © 1969, American Chemical Society. All rights reserved.