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Irreversible enzyme inhibitors. LXXXIII. Candidate active‐site‐directed irreversible inhibitors of dihydrofolic reductase. VIII. Derivatives of 2,4‐diaminopyrimidine. II
Author(s) -
Baker B. R.,
Jordaan Johannes H.
Publication year - 1967
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570040106
Subject(s) - chemistry , reductase , substituent , enzyme , active site , stereochemistry , pyrimidine , reagent , bromide , biochemistry , organic chemistry
2,4‐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 (NH 2 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.