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J. Biol. Chem., Vol. 280, Issue 28, 26397-26405, July 15, 2005

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7-Nitro-2,1,3-benzoxadiazole Derivatives, a New Class of Suicide Inhibitors for Glutathione S-Transferases

MECHANISM OF ACTION OF POTENTIAL ANTICANCER DRUGS^*

Giorgio Ricci, Francesca De Maria, Giovanni Antonini¶, Paola Turella, Angela Bullo, Lorenzo Stella, Giuseppe Filomeni||, Giorgio Federici**, and Anna Maria Caccuri

From the Departments of Chemical Sciences and Technologies and ^||Biology, University of Rome "Tor Vergata," 00133 Rome, the ^¶Department of Biology, University of Rome "Roma Tre," 00146 Rome, and the ^**Children's Hospital IRCCS "Bambin Gesù," 00165 Rome, Italy

Spectroscopic and rapid kinetic experiments were performed to detail the interaction of human glutathione S-transferases GSTA1-1, GSTM2-2, and GSTP1-1 with 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX). This compound is a representative molecule of a new class of 7-nitro-2,1,3-benzoxadiazole (NBD) derivatives (non-GSH peptidomimetic compounds) that have been designed both to give strong GST inhibition and to accumulate in tumor cells avoiding the extrusion mechanisms mediated by the multidrug resistance protein pumps. We have recently shown that submicromolar amounts of NBDHEX trigger apoptosis in several human tumor cell lines through the dissociation of the JNK·GSTP1-1 complex (Turella, P., Cerella, C., Filomeni, G., Bullo, A., De Maria, F., Ghibelli, L., Ciriolo, M. R., Cianfriglia, M., Mattei, M., Federici, G., Ricci, G., and Caccuri, A. M. (2005) Cancer Res. 65, 3751-3761). Results reported in the present study indicated that NBDHEX behaves like a suicide inhibitor for GSTs. It bound to the H-site and was conjugated with GSH forming a complex at the C-4 of the benzoxadiazole ring. This complex was tightly stabilized in the active site of GSTP1-1 and GSTM2-2, whereas in GSTA1-1 the release of the 6-mercapto-1-hexanol from the complex was the favored event. Docking studies demonstrated the likely localization of the complex in the GST active sites and provide a structural explanation for its strong stabilization.

Received for publication, March 25, 2005

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported in part by Ministero dell'Universitá e della Ricerca Scientifica e Tecnologica Grant COFIN2002.

To whom correspondence should be addressed: Dept. of Chemical Sciences and Technologies, University of Rome "Tor Vergata," Via della Ricerca Scientifica, 00133 Rome, Italy. Tel.: 39-0672594378; Fax: 39-0672594328; E-mail: caccuri{at}uniroma2.it.

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