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Structure-Activity Analysis of Tetrahydrofolate Analogs Using Substituent Constants and Regression Analysis

1967; Elsevier BV; Volume: 56; Issue: 1 Linguagem: Inglês

10.1002/jps.2600560119

1520-6017

Elinor Miller, Corwin Hansch,

Hemoglobin structure and function

The binding to dihydrofolate reductase of a series of substituted pyrimidines and tri-azines is shown to be dependent on the electron-contributing and lipophilic character of the substituents, as expressed by the parameters π and σ. The configuration of binding is variable, and is determined by the necessity of placing the most lipophilic substituent in a hydrophobic region of the enzyme. When two or more lipophilic substituents are present, competition between them for the hydrophobic site is dominated by the more lipophilic group, while the less lipophilic group contributes to hydrophobic bonding to a slight extent. Suggestions are made for the design of a new tetrahydrofolate analog with possible application as a nonclassical antimetabolite. The binding to dihydrofolate reductase of a series of substituted pyrimidines and tri-azines is shown to be dependent on the electron-contributing and lipophilic character of the substituents, as expressed by the parameters π and σ. The configuration of binding is variable, and is determined by the necessity of placing the most lipophilic substituent in a hydrophobic region of the enzyme. When two or more lipophilic substituents are present, competition between them for the hydrophobic site is dominated by the more lipophilic group, while the less lipophilic group contributes to hydrophobic bonding to a slight extent. Suggestions are made for the design of a new tetrahydrofolate analog with possible application as a nonclassical antimetabolite.