Irreversible enzyme inhibitors. LXXXIII. Candidate active‐site‐directed irreversible inhibitors of dihydrofolic reductase. VIII. Derivatives of 2,4‐diaminopyrimidine. II

Abstract

Abstract2,4‐Diamino‐6‐(p‐aminophenethyl)pyrimidines with a 5‐phenylbutyl (XIX) and 5‐(p‐chlorophenyl) (VIII) substituent were synthesized by condensation of the corresponding pyrimidine‐6‐carboxaldehydes (XVI, X) with the Wittig reagent derived from p‐nitro‐benzyl bromide, followed by catalytic hydrogenation. Selective bromoacetylation of VIII and XIX afforded the candidate active‐site‐directed irreversible inhibitors of dihydrofolic reductase, namely, 6‐(p‐bromoacetamidophenethyl)‐2,4‐diaminopyrimidine with a 5‐(p‐chlorophenyl)‐ (IV) and 5‐phenylbutyl‐ (III) substituents. Although III and IV were excellent reversible inhibitors of dihydrofolic reductase, neither showed any inactivation of the enzyme; in contrast, the corresponding 2‐amino‐6‐(p‐bromoacetamidophenethyl)‐5‐phenylbutyl‐4‐pyrimidinol (II) ‐ which differs from III only in the 4‐substituent (NH2 vs. OH) ‐ was an excellent active‐site‐directed irreversible inhibitor of dihydrofolic reductase, but II was a poor reversible inhibitor. Thus the conformations of II and III are most probably different when complexed to dihydrofolic reductase.