Design, Synthesis, and Evaluation of 2‐(arylsulfonyl)oxiranes as Cell‐permeable Covalent Inhibitors of Protein Tyrosine Phosphatases

Abstract

A structure-based design approach has been applied to develop 2-(arylsulfonyl)oxiranes as potential covalent inhibitors of protein tyrosine phosphatases. A detailed kinetic analysis of inactivation by these covalent inhibitors reveals that this class of compounds inhibits a panel of protein tyrosine phosphatases in a time-and dose-dependent manner, consistent with the covalent modification of the enzyme active site. An inactivation experiment in the presence of sodium arsenate, a known competitive inhibitor of protein tyrosine phosphatase, indicated that these inhibitors were active site bound. This finding is consistent with the mass spectrometric analysis of the covalently modified protein tyrosine phosphatase enzyme. Additional experiments indicated that these compounds remained inert toward other classes of arylphosphate-hydrolyzing enzymes, and alkaline and acid phosphatases. Cell-based experiments with human A549 lung cancer cell lines indicated that 2-(phenylsulfonyl)oxirane (1) caused an increase in intracellular pTyr levels in a dose-dependent manner thereby suggesting its cell-permeable nature. Taken together, the newly identified 2-(arylsulfonyl)oxiranyl moiety could serve as a novel chemotype for the development of activity-based probes and therapeutic agents against protein tyrosine phosphatase superfamily of enzymes.

Covalent inhibition of protein tyrosine phosphatases

“…Later, Dana and coworkers synthesized a small set of sulfonyloxiranyl derivatives based on molecular modeling studies. 149 Reaction of compounds 43–47 (Fig. 21) with PTP1B under pseudo first order kinetic conditions ([43] ≫ [PTP1B]) resulted in a time dependent loss of phosphatase activity.…”

Safe and Metal-Free Synthesis of 1-Alkenyl Aryl Sulfides and Their Sulfones from Thiiranes and Diaryliodonium Salts

“…After oxidation, all obtained sulfones 4 were in the transconfiguration, assigned by comparison with previously reported data. [28][29][30][31][32][33][34]…”

“…22 All of the sulfones are known compounds and have analytical data identical to the reported values. [28][29][30][31][32][33][34] [(E)-2-(Phenylsulfonyl)vinyl]benzene (4a) 28 White solid; yield: 42 mg (69%); mp 80-81 °C; R f = 0.18 (hexanes-EtOAc, 10:1).…”