Reactions of 1,3-Diketones with a Dipeptide Isothiazolidin-3-one: Toward Agents That Covalently Capture Oxidized Protein Tyrosine Phosphatase 1B

Abstract

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.

Reactivity, Selectivity, and Stability in Sulfenic Acid Detection: A Comparative Study of Nucleophilic and Electrophilic Probes

“…4C). 25, 57 Owing to poor reaction rate, 7a failed to capture Gpx3-SOH, a finding that was consistent with data obtained in the dipeptide-SOH model (Fig. 4D).…”

The role of sulfenic acids in cellular redox signaling: Reconciling chemical kinetics and molecular detection strategies

“…The molecular factors that control formation of sulfenyl amides are still unclear, but recent computational studies suggest that a constrained cysteine conformation within a β-loop-helix fold motif favors sulfenyl amide formation from initially generated Cys-SOH. [71] Importantly, recent studies using model sulfenyl amide compounds indicated that several dimedone-based reagents used to detect Cys-SOH are also reactive towards sulfenyl amides [26, 72], indicating that detection of dimedone-reactive proteins does not necessarily reflect the presence of Cys-SOH but may also indicate sulfenyl amides. Therefore, dimedone or chemically similar compounds are best considered molecular probes of for “two-electron oxidized cysteine species” representing either Cys-SOH or sulfenyl amides.…”

Rational design of reversible and irreversible cysteine sulfenic acid-targeted linear C-nucleophiles

“…Moreover, substitution by highly EWGs, such as –CF 3 , may lead to hydration of the carbonyl and complete loss of reactivity due an increase in C-3 carbanion p K a). 15 Subsequently, for nucleophiles of structural class 4 and 5 we postulated that replacing one or both carbonyls with a carboxylate ester, amide or hydrazide functionality would increase the p K a of the nucleophilic C-centre. Consistent with this hypothesis, we observed a marked decrease in reactive carbanion formation at physiological pH and a corresponding reduction in reactivity (Fig.…”