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Irreversible enzyme inhibitors. XCI. candidate active‐site directed irreversible inhibitors of thymidylate synthetase. II. 2‐amino‐6‐methyl‐5‐(p‐tolylsulfonamidopropyl)‐4‐pyrimidinols with N‐substituents on the sulfonamide moiety
Author(s) -
Baker B. R.,
Coward James K.
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.5570040207
Subject(s) - chemistry , iodoacetamide , sulfonamide , moiety , stereochemistry , thymidylate synthase , substituent , tosyl , enzyme , active site , amidine , biochemistry , cysteine , medicine , fluorouracil , surgery , chemotherapy
Three derivatives of 2‐amino‐6‐methyl‐5‐( p ‐tolylsulfonamidopropyl)‐4‐pyrimidinol (I) with N ‐ substituents on the sulfonamide group, namely bromoacetamidopropyl (XVI), m ‐bromoacetamidobenzyl (XXIVa), and p ‐bromoacetamidobenzyl (XXIVb), were synthesized as candidate active‐site‐directed irreversible inhibitors of thymidylate synthetase. The bromoacetamidopropyl derivative, (XVI), the p ‐bromoacetamidobenzyl derivative (XXIVb), and iodoacetamide showed irreversible inhibition of thymidylate synthetase, but XXIVa did not. Since iodoacetamide did inactivate the enzyme, but XXIVa did not, it cannot be ascertained whether XXIVb and XVI inactivate the enzyme by a random bimolecular mechanism or by the active‐site‐directed mechanism without evaluation of additional candidate inhibitors. Two synthetic routes were employed. The key intermediates for the bromoacetamidobenzyl sulfonamides (XXIV) were the corresponding nitrobenzyl sulfonamides (XXI); the latter were best prepared by reductive alkylation of 2‐amino‐5‐aminopropyl‐6‐methyl‐4‐pyrimidinol (XXV) with a nitrobenzaldehyde followed by tosylation. The key intermediate for XVI was a toluenesulfonamide with a carbobenzoxyaminopropyl substituent on the nitrogen (XIV); the latter was synthesized via N ‐carbobenzoxy‐ N' ‐tosyl‐1,3‐diaminopropane (XI).