Use of fluorinated functionality in enzyme inhibitor development: Mechanistic and analytical advantages

David B Berkowitz, Kannan R. Karukurichi, Roberto de la Salud-Bea, David L. Nelson, Christopher D. McCune

Research output: Contribution to journalReview article

64 Citations (Scopus)

Abstract

On the one hand, owing to its electronegativity, relatively small size, and notable leaving group ability from anionic intermediates, fluorine offers unique opportunities for mechanism-based enzyme inhibitor design. On the other, the "bio-orthogonal" and NMR-active 19-fluorine nucleus allows the bioorganic chemist to follow the mechanistic fate of fluorinated substrate analogues or inhibitors as they are enzymatically processed. This article takes an overview of the field, highlighting key developments along these lines. It begins by highlighting new screening methodologies for drug discovery that involve appropriate tagging of either the substrate or an array of potential substrates (i.e. in proteomics screens) with 19F-markers that then report back on turnover and function, respectively, via the NMR screen. Taking this one step further, substrate-tagging with fluorine can be done in such a manner as to provide stereochemical information on enzyme mechanism. For example, substitution of one of the terminal hydrogens in phosphoenolpyruvate, provides insight into the, otherwise latent, facial selectivity of C{single bond}C bond formation in KDO synthase. Perhaps, most importantly, from the point of view of this discussion, appropriately tailored fluorinated functionality can be used to form stabilized "transition state analogue" complexes with target enzymes. Thus, 5-fluorinated pyrimidines, α-fluorinated ketones, and 2-fluoro-2-deoxysugars each lead to covalent adduction of catalytic active site residues in thymidylate synthase (TS), serine protease and glycosidase enzymes, respectively. In all such cases, 19F NMR allows the bioorganic chemist to spectrally follow "transition state analogue" formation. Finally, the use of specific fluorinated functionality to engineer "suicide substrates" is highlighted in a discussion of the development of the α-(2′Z-fluoro)vinyl trigger for amino acid decarboxylase inactivation. Here 19F NMR allows the bioorganic chemist to glean useful partition ratio data directly from the NMR tube.

Original languageEnglish (US)
Pages (from-to)731-742
Number of pages12
JournalJournal of Fluorine Chemistry
Volume129
Issue number9
DOIs
StatePublished - Sep 1 2008

Fingerprint

enzyme inhibitors
Fluorine
Enzyme Inhibitors
nuclear magnetic resonance
inhibitor
Enzymes
Nuclear magnetic resonance
enzyme
fluorine
substrate
Catalytic Domain
Substrates
enzymes
tagging
Thymidylate Synthase
analogs
Pyrimidines
Phosphoenolpyruvate
Carboxy-Lyases
Glycoside Hydrolases

Keywords

  • 19-F NMR spectroscopy
  • Alpha-fluorinated ketones
  • Enzyme-activated inhibitors
  • Fluoro-sugars
  • Fluorovinyl amino acids
  • Mechanism-based inhibitors
  • Partition ratio
  • Suicide substrate
  • Transition state analogues
  • Trojan horse inhibitiors

ASJC Scopus subject areas

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

Cite this

Use of fluorinated functionality in enzyme inhibitor development : Mechanistic and analytical advantages. / Berkowitz, David B; Karukurichi, Kannan R.; de la Salud-Bea, Roberto; Nelson, David L.; McCune, Christopher D.

In: Journal of Fluorine Chemistry, Vol. 129, No. 9, 01.09.2008, p. 731-742.

Research output: Contribution to journalReview article

Berkowitz, David B ; Karukurichi, Kannan R. ; de la Salud-Bea, Roberto ; Nelson, David L. ; McCune, Christopher D. / Use of fluorinated functionality in enzyme inhibitor development : Mechanistic and analytical advantages. In: Journal of Fluorine Chemistry. 2008 ; Vol. 129, No. 9. pp. 731-742.
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