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

Aleem Gangjee, Hiteshkumar D. Jain, Jaclyn Phan, Xin Guo, Sherry Queener, Roy L. Kisliuk

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)953-961
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number2
DOIs
StatePublished - Jan 15 2010

Fingerprint

Folic Acid Antagonists
Pyrimidines
Tetrahydrofolate Dehydrogenase
Thymidylate Synthase
Pathogens
Pneumocystis carinii
Mycobacterium avium
Iodine
Saponification
Glutamic Acid
Scaffolds
Peptides
Acids
thymidylate synthase-dihydrofolate reductase
pyrimidine

Keywords

  • Dihydrofolate reductase
  • Dual inhibitors
  • Furo[2,3-d]pyrimidines
  • Thymidylate synthase

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

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. / Gangjee, Aleem; Jain, Hiteshkumar D.; Phan, Jaclyn; Guo, Xin; Queener, Sherry; Kisliuk, Roy L.

In: Bioorganic and Medicinal Chemistry, Vol. 18, No. 2, 15.01.2010, p. 953-961.

Research output: Contribution to journalArticle

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