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 sigma 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- mercapto1-hexanol from the sigma complex was the favored event. Docking studies demonstrated the likely localization of the sigma complex in the GST active sites and provide a structural explanation for its strong stabilization.

Ricci, G., De Maria, F., Antonini, G., Turella, P., Bullo, A., Stella, L., et al. (2005). 7-nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases - Mechanism of action of potential anticancer drugs. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 280(28), 26397-26405 [10.1074/jbc.M503295200].

7-nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases - Mechanism of action of potential anticancer drugs

RICCI, GIORGIO;STELLA, LORENZO;FILOMENI, GIUSEPPE;FEDERICI, GIORGIO;CACCURI, ANNA MARIA
2005-01-01

Abstract

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 sigma 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- mercapto1-hexanol from the sigma complex was the favored event. Docking studies demonstrated the likely localization of the sigma complex in the GST active sites and provide a structural explanation for its strong stabilization.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/10
English
Con Impact Factor ISI
Cells; Dissociation; Drug products; Molecules; Proteins; Spectroscopic analysis; Tumors; Human glutathione S-transferases; Protein pumps; Suicide inhibitor; Tumor cell lines; Derivatives; 6 (7 nitro 2,1,3 benzoxadiazol 4 ylthio)hexanol; 6 mercapto 1 hexanol; 7 nitro 2,1,3 benzoxadiazole derivative; antineoplastic agent; enzyme inhibitor; glutathione transferase; glutathione transferase A1; glutathione transferase m2 2; glutathione transferase P1 1; hexanol; multidrug resistance protein; oxadiazole derivative; stress activated protein kinase; thiol derivative; unclassified drug; apoptosis; article; cancer cell culture; dissociation; drug accumulation; drug conjugation; drug mechanism; drug structure; enzyme active site; enzyme binding; enzyme inhibition; enzyme inhibitor complex; enzyme inhibitor interaction; human; human cell; IC 50; molecular stability; priority journal; spectroscopy; tumor cell; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Design; Drug Resistance, Multiple; Enzyme Inhibitors; Glutathione Transferase; Hexanols; Humans; K562 Cells; Kinetics; Microscopy, Fluorescence; Models, Chemical; Models, Molecular; Oxadiazoles; Peptides; Piperazines; Protein Binding; Protein Conformation; Spectrometry, Fluorescence; Spectrophotometry; Sulfhydryl Compounds; Temperature; Time Factors
Ricci, G., De Maria, F., Antonini, G., Turella, P., Bullo, A., Stella, L., et al. (2005). 7-nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases - Mechanism of action of potential anticancer drugs. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 280(28), 26397-26405 [10.1074/jbc.M503295200].
Ricci, G; De Maria, F; Antonini, G; Turella, P; Bullo, A; Stella, L; Filomeni, G; Federici, G; Caccuri, Am
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/30907
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