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')

Journal of Medicinal Chemistry

Volumn 47, Issue 16, 2004, Pages 4105-4108

  Richardson, Marianne L ^a   Croughton, Karen A ^a   Matthews, Charles S ^a   Stevens, Malcolm F G ^a  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

DICHLOROBENZOPRIM; DIHYDROFOLATE REDUCTASE; DIHYDROFOLATE REDUCTASE INHIBITOR; METHOTREXATE; METHYLBENZOPRIM; PYRIMIDINE DERIVATIVE; TRIMETREXATE; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL CULTURE; CANCER INHIBITION; CELL STRAIN HT29; ENZYME INHIBITION; HUMAN; HUMAN CELL; STRUCTURE ACTIVITY RELATION;

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;

EID: 3242797370     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm040785+     Document Type: Article

References (14)

1. Hannah, D. R.; Stevens, M. F. G. Structural studies on bioactive compounds. Part 38. Reactions of 5-aminoimidazole-4-carboxamide: synthesis of imidazo[1,5-α]quinazolin-3-carboxamides. J. Chem. Res. (S) 2003, 398-401.
2. Griffin, R. J.; Meek, M. A.; Schwalbe, C. H.; Stevens, M. F. G. Structural studies on bioactive compounds. 8. Synthesis, crystal structure, and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line. J. Med. Chem. 1989, 32, 2468-2474.
3. Croughton, K. A.; Matthews, C. S.; Griffin, R. J.; Stevens, M. F. G. Investigations on the biological properties of the lipophilic DHFR-inhibitory benzoprims reveal nonfolate modes of action and opportunities for anti-cancer drug design. Anti-Cancer Drug Des. 2001, 16, 119-128.
4. Weinstein, J. N.; Myers, T. G.; O'Connor, P. M.; Friend, S. H.; Fornace, A. J.; Kohn, K. W.; Fojo, T.; Bates, S.; Rubinstein, V.; Anderson, N. L.; Buolamwini, J. K.; van Osdol, W. W.; Monks, A.; Scudiero, D. A.; Sausville, E. A.; Zaharevitz, D. W.; Bunow, B.; Viswanadhan, V. N.; Johnson, G. S.; Wittes, R. E.; Paull, K. D. An information-intensive approach to the molecular pharmacology of cancer. Science 1997, 275, 343-349.
5. Paull, K. D.; Hamel, E.; Malspeis, L. Prediction of biochemical mechanism of action from the in vitro antitumor screen of the National Cancer Institute. In Cancer Chemotherapeutic Agents; Foye, W. O., Ed.; American Chemical Society: Washington, DC, 1995; pp 9-45.
6. Ho, Y. K.; Hakala, M. T.; Zakrezewski, S. G. 5-(1-Adamantyl)-pyrimidines as inhibitors of folate metabolism. Cancer Res. 1972, 32, 1023-1028.
7. Gangjee, A.; Vasudevan, A.; Queener, S. F. Conformationally restricted analogues of trimethoprim: 2,6-diamino-8-substituted purines as potential dihydrofolate reductase inhibitors from Pneumocyctis carinii and Toxoplasma gondii. J. Med. Chem. 1997, 40, 3032-3039.
8. Griffin, R. J.; Stevens, M. F. G.; Sansom, C. E. Structural studies on bioactive compounds. Part 16. Synthesis and properties of sterically constrained analogues of methylbenzoprim, a new dihydrofolate reductase inhibitor Anti-Cancer Drug Des. 1990, 5, 201-211.
9. Greco, W. R.; Hakala, M. T. Biochemical pharmacology of lipophilic diaminopyrimidine antifolates in mouse and human cells in vitro. Mol. Pharmacol. 1980, 18, 521-528.
10. Smith, D. M. In Benzimidazoles and Congeneric Tricyclic Compounds; Preston, P. N., Ed.; John Wiley & Sons: New York, 1981; pp 287-330.
11. Baker, B. R. In Design of Active-Site-Directed Irreversible Enzyme Inhibitors; John Wiley: New York, 1967.
12. Machin, J.; Mackie, R. K.; McNab, H.; Reed, G. A.; Sagar, A. J. G.; Smith, D. M. o-Nitroaniline derivatives. Part V. Cyclisation of N-acylated derivatives of N-benzyl- and N-p-nitrobenzyl-o-nitroaniline: a comparison of carboxamides and sulphonamides. J. Chem. Soc., Perkin Trans. 1 1976, 394-399.
13. Richardson, M. L.; Stevens, M. F. G. Structural studies on bioactive compounds. Part 37. Suzuki coupling of diaminopyrimidines: a new synthesis of the antimalarial drug pyrimethamine. J. Chem. Res. (S) 2002, 482-484.
14. Bliss, E. A.; Griffin, R. J.; Stevens, M. F. G. Structural studies on bioactive compounds. Part 5. Synthesis and properties of 2,4-diaminopyrimidine dihydrofolate reductase inhibitors bearing lipophilic azido groups. J. Chem. Soc., Perkin Trans. 1 1987, 2217-2228.