Synthesis and biological evaluation of Nα-(4-amino-4-deoxy-10-methylpteroyl)-DL-4,4-difluoroornithine

Takashi Tsukamoto, William H. Haile, John J. McGuire, James K. Coward

Research output: Contribution to journalReview articlepeer-review

Abstract

N α-(4-Amino-4-deoxy-10-methylpteroyl)-DL-4,4-difluoroornithine (AMPte-DL-4,4-F2Orn, 4) was synthesized and evaluated as an inhibitor of human folylpoly-γ-glutamate synthetase (FPGS), dihydrofolate reductase (DHFR), and cell growth. Synthesis of 4 involved the use of a protected form of DL-4,4-difluoroornithine 9 which was derived from DL-4,4-difluoroglutamic acid. Biological activities of 4 were compared directly to those of the corresponding nonfluorinated compound Nα-(4-amino-4-deoxy-10-methylpteroyl)-L-ornithine (AMPte-L-Orn, 3). Although the fluorinated analogue is a potent inhibitor of DHFR, it is a poor inhibitor of FPGS. However, the compound is transported across the cell membrane and inhibits cell growth, presumably due to the inhibition of DHFR. The data obtained with the fluorinated analogue are in contrast to those of the corresponding nonfluorinated compound 3, which is a potent inhibitor of both FPGS and DHFR but shows very low cytotoxicity due to poor transport.

Original languageEnglish (US)
Pages (from-to)2536-2540
Number of pages5
JournalJournal of medicinal chemistry
Volume39
Issue number13
DOIs
StatePublished - Jun 21 1996
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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