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Analogs of tetrahydrofolic acid. XIII. On the mode of binding of the anilino group of 2‐amino‐5‐(3‐anilinopropyl)‐6‐methyl‐4‐pyrimidinol to dihydrofolic reductase and thymidylate synthetase
Author(s) -
Baker B. R.,
Ho BengThong,
Chheda Girish B.
Publication year - 1964
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.5570010207
Subject(s) - chemistry , thymidylate synthase , stereochemistry , protonation , enzyme , methyl group , ring (chemistry) , acceptor , electron acceptor , medicinal chemistry , biochemistry , group (periodic table) , organic chemistry , ion , medicine , fluorouracil , physics , surgery , chemotherapy , condensed matter physics
Six analogs of 2‐amino‐5‐(3‐anilinopropyl)‐6‐methyl‐4‐pyrimidinol (II) with modifications in the anilino group have been synthesized in order to shed light on the mode of binding of the anilino group to dihydrofolic reductase and thymidylate synthetase. Replacement of the anilino group of II with n ‐butylamino (XI) led to great decrease in binding, indicating that the anilino group did not bind to these enzymes in the protonated form. Replacement of the anilino group of II with benzyl gave a compound (XIIb) which was a 26‐fold and 1.5‐fold better inhibitor of dihydrofolic reductase and thymidylate synthetase, respectively; these results indicated that the NH portion of the anilino group contributed less to the enzyme binding than did the benzene ring, and that the latter probably was bound as an electron acceptor in a charge‐transfer complex to an electron‐rich locus on the enzyme. Further evidence was also obtained that the benzene ring was complexing as an electron acceptor by placement of electron‐donating or electron‐withdrawing groups on the p ‐positions of anilino group, and by N‐acetylation of the anilino group.