IRREVERSIBLE ENZYME INHIBITORS .160. SOME FACTORS IN CELL WALL TRANSPORT OF ACTIVE-SITE-DIRECTED IRREVERSIBLE INHIBITORS OF DIHYDROFOLIC REDUCTASE DERIVED FROM 4,6-DIAMINO-1,2-DIHYDRO-2,2-DIMETHYL-L-(PHENYLALKYLPHENYL)-S-TRIAZINES

A series of nine derivatives of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-phenyl-s-triazines bearing a phenylbutyl, phenethyl, or phenoxybutyl side chain on the meta or para position of the benzene ring were evaluated as inhibitors of L1210 cell culture; several of these compounds were excellent inhibitors that showed 50% cell kill in the 10-9-10-10 M concentration range and had I50 = 6Ki for L1210 dihydrofolic reductase of about 10-8 M. When these phenylalkyl derivatives were substituted with an SO2F group, some potent irreversible inhibitors were obtained that could inactivate L1210 dihydrofolic reductase >80%. in 2 min or less; for example, the p-fluorosulfonylphenylbutyl substituent on the meta position (19) had I50 = 6Ki = 8 × 10-9 M, and at 6 × 10-8 M gave 86% inactivation of the L1210 enzyme in <2 min, but also inactivated the mouse liver enzyme. It is estimated that the polar SO2F moiety slows passive diffusion about 40-fold, but increases effectiveness on the target enzyme, dihydrofolic reductase, by about 200-fold. © 1969, American Chemical Society. All rights reserved.