Structural studies on bioactive compounds. 39. Biological consequences of the structural modification of DHFR-inhibitory 2,4-diamino-6-(4-substituted benzylamino-3-nitrophenyl)-6-ethylpyrimidines ('benzoprims').

Marianne L Richardson; Karen A Croughton; Charles S Matthews; Malcolm F G Stevens

doi:10.1021/jm040785+

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Structural studies on bioactive compounds. 39. Biological consequences of the structural modification of DHFR-inhibitory 2,4-diamino-6-(4-substituted benzylamino-3-nitrophenyl)-6-ethylpyrimidines ('benzoprims').

Marianne L Richardson·Karen A Croughton·Charles S Matthews·Malcolm F G Stevens

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Abstract

Benzimidazole-N-oxide modifications of potent lipophilic dihydrofolate reductase (DHFR) inhibitors (e.g., methylbenzoprim 1 and dichlorobenzoprim 2) have been prepared by base-promoted cyclization of the nitrophenylbenzylamino groups to explore the possibility that abrogation of DHFR-inhibitory activity might reveal clues to an alternative anti-ras mechanism. Examples of the new series had only low growth inhibitory activities (GI(50) generally >50 microM) against colon HCT116 and lung HT29 cell lines but, unlike methylbenzoprim, this activity was unaffected by hypoxanthine/thymidine rescue.

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Antineoplastic Agents Benzylamines Cell Division Cell Line, Tumor Cyclization Drug Screening Assays, Antitumor Folic Acid Antagonists Humans Protein Binding Pyrimidines Structure-Activity Relationship Tetrahydrofolate Dehydrogenase Journal Article Research Support, Non-U.S. Gov't

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Marianne L Richardson, Karen A Croughton, Charles S Matthews, Malcolm F G Stevens. 2004-07-29. Structural studies on bioactive compounds. 39. Biological consequences of the structural modification of DHFR-inhibitory 2,4-diamino-6-(4-substituted benzylamino-3-nitrophenyl)-6-ethylpyrimidines ('benzoprims').. https://doi.org/10.1021/jm040785%2B

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