An improved preparation of the activity-based probe JPM-OEt and in situ applications

A short, stereoselective synthesis of the general, cell permeable cathepsin probe JPM-OEt, is presented. The synthetic route is improved and described in more detail than previous reports for related compounds. This serves as a facile method for the synthesis of multi-gram quantities of activity-based probes utilizing an epoxide-succinyl scaffold. Additionally, JPM-OEt is shown to be cell permeable, allowing in vivo characterization of cysteine proteases. More importantly, this reagent has recently been shown to be an effective general inhibitor of papain family cysteine proteases in animal models of cancer. For this reason the outlined synthesis method will enable future in vivo studies using this reagent.