(α-Monofluoroalkyl)phosphonates: A class of isoacidic and "tunable" mimics of biological phosphates

David B. Berkowitz, Mohua Bose

Research output: Contribution to journalArticle

125 Scopus citations

Abstract

In the early 1980s, Blackburn and McKenna suggested that α-fluorination might lead to phosphonates that better mimic natural phosphates. Although α-monofluorination produces phosphonates with "matching" second pKa values, the α,α-difluorinated phosphonates have received more attention in the past decade or so. Recently, reported enzyme kinetic data on the α-monofluorinated phosphonates from the O'Hagan lab and from our lab suggest that the CHF stereochemistry does affect enzyme-binding, thereby providing an additional variable that may be tuned to achieve optimal binding to an active site of interest. This asymmetry also appears in structural data from the groups of Barford/Burke and Tracey on PTP1B complexes with bound α,α-difluorinated phosphonate inhibitors. In those complexes, only one of two prochiral fluorine atoms appears to interact appreciably with the enzyme. Namely, it is thought that the pro-R (Fsi) fluorine is engaged in an important hydrogen bond with the Phe-182 amide NH. Available methods for the synthesis of this class of α-monofluorinated phosphonates are reviewed. A new convergent approach, developed at Nebraska, in which the potassium anion of (α-fluoro-α-phenylsulfonylmethyl)phosphonate is used to displace primary triflates is also described. This method is particularly convenient as it allows one to perform a "fluorinated phosphonate scan" of an active site of interest (in what follows, we use this expression to designate the synthesis and evaluation of a complete set of the CH2-, CF2- and both stereoisomeric CHF-phosphonates in an active site of interest) from a single primary triflate. The properties of the title compounds in enzyme active sites are discussed, as are possible interactions of these fluorine-containing bioisosteres with active site residues.

Original languageEnglish (US)
Pages (from-to)13-33
Number of pages21
JournalJournal of Fluorine Chemistry
Volume112
Issue number1
DOIs
StatePublished - 2001

Keywords

  • (α-Monofluoroalkyl)phosphonate
  • Glucose 6-phosphate dehydrogenase
  • Glycerol 3-phosphate dehydrogenase
  • Phosphate mimics
  • Protein phosphotyrosine phosphatase PTP1B
  • Triflate displacement

ASJC Scopus subject areas

  • Biochemistry
  • Environmental Chemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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