Nitrobenzoxadiazole-based GSTP1-1 inhibitors containing the full peptidyl moiety of (pseudo)glutathione.
BACKGROUND
The inhibition of glutathione S-transferase P1-1 (GSTP1-1) is a sound strategy to overcome drug resistance in oncology practice.


OBJECTIVE
The nitrobenzoxadiazolyl (NBD) S-conjugate of glutathione and the corresponding γ-oxa-glutamyl isostere (compounds 1 and 5, respectively) have been disclosed as GST inhibitors. The rationale of their design is discussed in juxtaposition to non-peptide NBD thioethers.


METHODS
Synthesis of derivatives 1 and 5 and in vitro evaluation on human GSTP1-1 and M2-2 are reported.


RESULTS
Conjugates 1 and 5 were found to be low micromolar inhibitors of both isoforms. Furthermore, they display a threefold reduction in selectivity for GSTM2-2 over the P1-1 isozyme in comparison with the potent non-peptide inhibitor nitrobenzoxadiazolyl-thiohexanol (NBDHEX).


CONCLUSIONS
Spectroscopic data are congruent with the formation of a stable sigma-complex between GSH and the inhibitors in the protein active site. Conjugate 5 is suitable for in vivo modulation of GST activity in cancer treatment.
a Department of Pharmacy , "Gabriele d'Annunzio" University , Chieti , Italy .
Grazia
G
Luisi
a Department of Pharmacy , "Gabriele d'Annunzio" University , Chieti , Italy .
Adriano
A
Mollica
a Department of Pharmacy , "Gabriele d'Annunzio" University , Chieti , Italy .
Simone
S
Carradori
b Department of Drug Chemistry and Technologies , "Sapienza" University , Rome , Italy .
Alessia
A
Lenoci
c The NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata , Rome , Italy , and.
Anastasia
A
De Luca
c The NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata , Rome , Italy , and.|d Department of Experimental Medicine and Surgery , University of Tor Vergata , Rome , Italy.
Anna Maria
AM
Caccuri
D009327:4-Chloro-7-nitrobenzofurazan / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005978:Glutathione / Q000737:chemistry / Q000494:pharmacology*; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C412602:glutathione S-transferase Mu 2; D009327:4-Chloro-7-nitrobenzofurazan; D005978:Glutathione
Glutathione S-conjugates; glutathione S-transferases; nitrobenzoxadiazole S-derivatives; pseudopeptide; urethane bond