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Synthesis 2005(2): 240-244  
DOI: 10.1055/s-2004-837295
PAPER
© Georg Thieme Verlag Stuttgart · New York

An Improved Preparation of the Activity-Based Probe JPM-OEt and In Situ Applications

Kareem A. H. Chehadea,1, Amos Barucha,1, Steven H. L. Verhelstb, Matthew Bogyo*a,b
a Department of Biochemistry and Biophysics, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, California 94143, USA
b Department of Pathology, Stanford University School of Medicine, Edwards Building, Room R-343, 300 Pasteur Drive, Stanford, CA 94305, USA
Fax: +1(650)7257424; e-Mail: mbogyo@stanford.edu;
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Publikationsverlauf

Received 13 August 2004
Publikationsdatum:
22. Dezember 2004 (online)

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Abstract

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.

Key words

epoxides - medicinal chemistry - inhibitors - cysteine proteases - activity based probes

1

Current address: Department of Chemical Proteomics, Celera 180 Kimball Way, South San Francisco, CA, USA.

28

Chehade, K. A. H.; Huang, J.; Verhelst, S. H. L.; Bogyo, M. unpublished results.