The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents.
Article Details
- CitationCopy to clipboard
Gangjee A, Jain HD, Queener SF, Kisliuk RL
The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents.
J Med Chem. 2008 Aug 14;51(15):4589-600. doi: 10.1021/jm800244v. Epub 2008 Jul 8.
- PubMed ID
- 18605720 [ View in PubMed]
- Abstract
Novel classical antifolates (3 and 4) and 17 nonclassical antifolates (11-27) were synthesized as antitumor and/or antiopportunistic infection agents. Intermediates for the synthesis of 3, 4, and 11-27 were 2,4-diamino-5-alkylsubstituted-7H-pyrrolo[2,3-d]pyrimidines, 31 and 38, prepared by a ring transformation/ring annulation sequence of 2-amino-3-cyano-4-alkyl furans to which various aryl thiols were attached at the 6-position via an oxidative addition reaction using I2. The condensation of alpha-hydroxy ketones with malonodinitrile afforded the furans. For the classical analogues 3 and 4, the ester precursors were deprotected, coupled with diethyl-L-glutamate, and saponified. Compounds 3 (IC50 = 60 nM) and 4 (IC50 = 90 nM) were potent inhibitors of human DHFR. Compound 3 inhibited tumor cells in culture with GI50
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Methotrexate Dihydrofolate reductase IC 50 (nM) 22 N/A N/A Details Methotrexate Thymidylate synthase IC 50 (nM) 29000 N/A N/A Details Pyrimethamine Dihydrofolate reductase IC 50 (nM) 6000 N/A N/A Details Trimethoprim Dihydrofolate reductase IC 50 (nM) 680000 N/A N/A Details