7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases. Mechanism of action of potential anticancer drugs.
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-mercapto-1-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
Giorgio
G
Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, 00133 Rome, Italy.
De Maria
Francesca
F
Antonini
Giovanni
G
Turella
Paola
P
Bullo
Angela
A
Stella
Lorenzo
L
Filomeni
Giuseppe
G
Federici
Giorgio
G
Caccuri
Anna Maria
AM
D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000441:Hexanols / Q000737:chemistry; D006801:Humans; D020014:K562 Cells; D007700:Kinetics; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D008958:Models, Molecular; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D013050:Spectrometry, Fluorescence; D013053:Spectrophotometry; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013696:Temperature; D013997:Time Factors
C432126:4-nitro-7-piperazino-2,1,3-benzoxadiazole; C503488:6-mercapto-1-hexanol; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000441:Hexanols; D010069:Oxadiazoles; D010455:Peptides; D010879:Piperazines; D013438:Sulfhydryl Compounds; D005982:Glutathione Transferase