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Synthesis and antifolate activity of new pyrrolo[2,3‐ d ]pyrimidine and thieno[2,3‐ d ]pyrimidine inhibitors of dihydrofolate reductase
Author(s) -
Vaidya Chitra,
Wright Joel E.,
Rosowsky Andre
Publication year - 2004
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.5570410523
Subject(s) - antifolate , dihydrofolate reductase , chemistry , aminopterin , pyrimidine , ornithine , stereochemistry , biochemistry , pteridine , methotrexate , enzyme , amino acid , antimetabolite , arginine , biology , organic chemistry , toxicity , immunology
Abstract Three previously undescribed dihydrofolate reductase (DHFR) inhibitors, N α ‐[4‐[ N ‐[(2,4‐diaminopyrrolo[2,3‐ d ]pyrimidin‐5‐yl)methyl]amino]benzoyl]‐ N δ ‐hemiphthaloyl‐L‐ornithine (7) , N α ‐ [4‐ [ N ‐[(2,4‐diaminothieno[2,3‐ d ]pyrimidin‐5‐yl)methyl]amino]benzoyl]‐ N δ ‐hemiphthaloyl‐L‐ornithine (8) , and N ‐[4‐[ N ‐[(2,4‐diaminothieno[2,3‐ d ]pyrimidin‐5‐yl)methyl]amino]benzoyl]‐L‐glutamic acid (12) , were synthesized and their antifolate activity was assessed. The ability of 7 and 8 to bind to DHFR and inhibit the growth of CCRF‐CEM human lymphoblastic leukemia cells in culture were dramatically reduced in comparison with the corresponding pteridine analogue, N α ‐(4‐amino‐4‐deoxypteroyl)‐ N δ ‐hemiphmaloyl‐L‐ornithine ( 1 , PT523). In a similar manner, the antifolate activity of 12 was markedly reduced in comparison with that of the corresponding glutamate analogue, aminopterin ( 5 , AMT). In contrast, 7, 8 , and 12 all displayed excellent affinity for the reduced folate carrier (RFC) of CCRF‐CEM cells as measured by a standard competitive influx assay. Lack of a consistent correlation between the results of the growth inhibition assays and those of the DHFR and RFC binding assays results suggest that additional factors also play a role in the antifolate activity of these compounds.