Back to Search
Start Over
Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1'-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators.
- Source :
-
Journal of the American Chemical Society [J Am Chem Soc] 2017 Oct 11; Vol. 139 (40), pp. 14077-14089. Date of Electronic Publication: 2017 Sep 28. - Publication Year :
- 2017
-
Abstract
- Developing specific chemical functionalities to deploy in biological environments for targeted enzyme inactivation lies at the heart of mechanism-based inhibitor development but also is central to other protein-tagging methods in modern chemical biology including activity-based protein profiling and proteolysis-targeting chimeras. We describe here a previously unknown class of potential PLP enzyme inactivators; namely, a family of quaternary, α-(1'-fluoro)vinyl amino acids, bearing the side chains of the cognate amino acids. These are obtained by the capture of suitably protected amino acid enolates with β,β-difluorovinyl phenyl sulfone, a new (1'-fluoro)vinyl cation equivalent, and an electrophile that previously eluded synthesis, capture and characterization. A significant variety of biologically relevant AA side chains are tolerated including those for alanine, valine, leucine, methionine, lysine, phenylalanine, tyrosine, and tryptophan. Following addition/elimination, the resulting transoid α-(1'-fluoro)-β-(phenylsulfonyl)vinyl AA-esters undergo smooth sulfone-stannane interchange to stereoselectively give the corresponding transoid α-(1'-fluoro)-β-(tributylstannyl)vinyl AA-esters. Protodestannylation and global deprotection then yield these sterically encumbered and densely functionalized quaternary amino acids. The α-(1'-fluoro)vinyl trigger, a potential allene-generating functionality originally proposed by Abeles, is now available in a quaternary AA context for the first time. In an initial test of this new inhibitor class, α-(1'-fluoro)vinyllysine is seen to act as a time-dependent, irreversible inactivator of lysine decarboxylase from Hafnia alvei. The enantiomers of the inhibitor could be resolved, and each is seen to give time-dependent inactivation with this enzyme. Kitz-Wilson analysis reveals similar inactivation parameters for the two antipodes, L-α-(1'-fluoro)vinyllysine (K <subscript>i</subscript> = 630 ± 20 μM; t <subscript>1/2</subscript> = 2.8 min) and D-α-(1'-fluoro)vinyllysine (K <subscript>i</subscript> = 470 ± 30 μM; t <subscript>1/2</subscript> = 3.6 min). The stage is now set for exploration of the efficacy of this trigger in other PLP-enzyme active sites.
- Subjects :
- Amino Acids chemistry
Amino Acids pharmacology
Cations chemical synthesis
Cations chemistry
Cations pharmacology
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Halogenation
Lysine chemical synthesis
Lysine pharmacology
Models, Molecular
Vinyl Compounds chemistry
Vinyl Compounds pharmacology
Amino Acids chemical synthesis
Carboxy-Lyases antagonists & inhibitors
Enzyme Inhibitors chemical synthesis
Hafnia alvei enzymology
Lysine analogs & derivatives
Vinyl Compounds chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-5126
- Volume :
- 139
- Issue :
- 40
- Database :
- MEDLINE
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Academic Journal
- Accession number :
- 28906111
- Full Text :
- https://doi.org/10.1021/jacs.7b04690