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Analogs of tetrahydrofolic acid. XXIX. Hydrophobic bonding to dihydrofolic reductase. II. On the mode of phenyl binding of 1‐aryl‐4,6‐diamino‐1,2‐dihydro‐2,2‐dimethyl‐s‐triazines
Author(s) -
Baker B. R.,
Ho BengThong
Publication year - 1965
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.5570020402
Subject(s) - chemistry , steric effects , aryl , stereochemistry , cationic polymerization , triazine , hydrogen bond , ring (chemistry) , enzyme , organic chemistry , molecule , alkyl
Abstract The inhibition of dihydrofolic reductase by twenty appropriately 1‐substituted‐4, 6‐diamino‐1, 2 ‐ dihydro‐2, 2‐dimethyl‐ s ‐triazines were compared in order to shed light on the mode of phenyl binding of 1‐aryl‐1,2‐dihydro‐ s ‐triazines. When the 1‐phenyl group was substituted by a cationic group at the 4‐position or an anionic group at either the 3‐ or 4‐position, a large loss in affinity by the enzyme for the resultant inhibitor was noted. This loss in affinity is best explained by the concept that the 1‐aryl group complexes with a hydrophobic region on the enzyme and that the hydrophobic region repels any aryl group bearing either a positively or negatively charged group. p ‐Substituents coplanar with the 1‐aryl group caused a steric interaction with the enzyme resulting in considerable loss in binding to this enzyme isolated from pigeon liver; this steric effect was considerably less in the m ‐position. Inductive effects of 1‐phenyl substituents on a possible charge‐transfer complex of the 1‐aryl group or on the binding ability of the 4,6‐diamino‐1,2‐dihydro‐ s ‐triazine ring system could not be correlated with the Hammett sigma‐values; therefore these effects were considered to be of minor importance.