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').
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.
Richardson
Marianne L
ML
Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK.
Croughton
Karen A
KA
Matthews
Charles S
CS
Stevens
Malcolm F G
MF
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001596:Benzylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003500:Cyclization; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
D000970:Antineoplastic Agents; D001596:Benzylamines; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase