Synthesis and biological evaluation of DL-4,4-difluoroglutamic acid and DL-γ,γ-difluoromethotrexate

Takashi Tsukamoto, Tomoya Kitazume, John J. McGuire, James K. Coward

Research output: Contribution to journalArticle

Abstract

DL-4,4-Difluoroglutamic acid (DL-4,4-F2Glu) and its methotrexate analogue, DL-γ,γ-difluoromethotrexate (DL-γ,γ-F2MTX), were synthesized and evaluated as alternate substrates or inhibitors of folate-dependent enzymes. Synthesis of DL-4,4-F2Glu involved the nitroaldol reaction of ethyl nitroacetate with a difluorinated aldehyde ethyl hemiacetal as a key step. Attempted ligation of DL-4,4-F2Glu to methotrexate (MTX), catalyzed by human folylpoly-γ-glutamate synthetase (FPGS), revealed that DL-4,4-F2Glu is a poor alternate substrate. DL-γ,γ-F2MTX was synthesized by a route proceeding through N-[4-(methylamino)benzoyl]-4,4-difluoroglutamic acid di- tert-butyl ester followed by alkylation with 6-(bromomethy])-2,4- pteridinediamine hydrobromide. DL-γ,γ-F2MTX was found to be neither a substrate nor an inhibitor of human FPGS. The fluorinated analogue of MTX, however, inhibits DHFR and cell growth with the same potency as MTX.

Original languageEnglish (US)
Pages (from-to)66-72
Number of pages7
JournalJournal of medicinal chemistry
Volume39
Issue number1
DOIs
StatePublished - Jan 5 1996

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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