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2,4-Diamino-5-methyl-6-substituted arylthio-furo[2,3-d]pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors
Bioorganic & Medicinal Chemistry
  • Aleem Gangjee, Duquesne University
  • Hiteshkumar D. Jain, Duquesne University
  • Jaclyn Phan, Duquesne University
  • Xin Guo, Duquesne University
  • Sherry F. Queener, Indiana University
  • Roy L. Kisliuk, Tufts University
Document Type
Article
DOI
10.1016/j.bmc.2009.11.029
Publication Date
1-1-2010
Abstract
A novel classical antifolate N-{4-[(2,4-diamino-5-methyl-furo[2,3-d]pyrimidin-6-yl)thio]-benzoyl}-l-glutamic acid 5 and 11 nonclassical antifolates 6–16 were designed, synthesized, and evaluated as inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The nonclassical compounds 6–16 were synthesized from 20 via oxidative addition of substituted thiophenols using iodine. Peptide coupling of the intermediate acid 21 followed by saponification gave the classical analog 5. Compound 5 is the first example, to our knowledge, of a 2,4-diamino furo[2,3-d]pyrimidine classical antifolate that has inhibitory activity against both human DHFR and human TS. The classical analog 5 was a nanomolar inhibitor and remarkably selective inhibitor of Pneumocystis carinii DHFR and Mycobacterium avium DHFR at 263-fold and 2107-fold, respectively, compared to mammalian DHFR. The nonclassical analogs 6–16 were moderately potent against pathogen DHFR or TS. This study shows that the furo[2,3-d]pyrimidine scaffold is conducive to dual human DHFR-TS inhibitory activity and to high potency and selectivity for pathogen DHFR.
Citation Information
Aleem Gangjee, Hiteshkumar D. Jain, Jaclyn Phan, Xin Guo, et al.. "2,4-Diamino-5-methyl-6-substituted arylthio-furo[2,3-d]pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors" Bioorganic & Medicinal Chemistry Vol. 18 Iss. 2 (2010) p. 953 - 961 ISSN: 0968-0896
Available at: http://works.bepress.com/xin-guo/25/