1 research outputs found
Reactions of 1,3-Diketones with a Dipeptide Isothiazolidin-3-one: Toward Agents That Covalently Capture Oxidized Protein Tyrosine Phosphatase 1B
Protein tyrosine phosphatase 1B (PTP1B)
is a validated therapeutic
target for the treatment of type 2 diabetes; however, the enzyme has
been classified by some as an “undruggable target”.
Here we describe studies directed toward the development of agents
that covalently capture the sulfenyl amide “oxoform”
of PTP1B generated during insulin signaling events. The sulfenyl amide
residue found in oxidized PTP1B presents a unique electrophilic sulfur
center that may be exploited in drug and probe design. Covalent capture
of oxidized PTP1B could permanently disable the intracellular pool
of enzyme involved in regulation of insulin signaling. Here, we employed
a dipeptide model of oxidized PTP1B to investigate the nucleophilic
capture of the sulfenyl amide residue by structurally diverse 1,3-diketones.
All of the 1,3-diketones examined here reacted readily with the electrophilic
sulfur center in the sulfenyl amide residue to generate stable covalent
attachments. Several different types of products were observed, depending
upon the substituents present on the 1,3-diketone. The results provide
a chemical foundation for the development of agents that covalently
capture the oxidized form of PTP1B generated in cells during insulin
signaling events