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

Aleem Gangjee, Hiteshkumar D. Jain, Sherry F. Queener, Roy L. Kisliuk

Research output: Contribution to journalArticle

28 Scopus citations

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 α-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 ≤ 10-7 M. Nonclassical 17 (IC 50 = 58 nM) was a potent inhibitor of Toxoplasma gondii (T. gondii) DHFR with > 500-fold selectivity over human DHFR. Analogue 17 was 50-fold more potent than trimethoprim and about twice as selective against T. gondii DHFR.

Original languageEnglish (US)
Pages (from-to)4589-4600
Number of pages12
JournalJournal of Medicinal Chemistry
Volume51
Issue number15
DOIs
StatePublished - Aug 14 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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