1. Nitrobenzoxadiazole-based GSTP1-1 inhibitors containing the full peptidyl moiety of (pseudo)glutathione.
- Author
-
Luisi, Grazia, Mollica, Adriano, Carradori, Simone, Lenoci, Alessia, De Luca, Anastasia, and Caccuri, Anna Maria
- Subjects
NITROBENZOIC acid ,GLUTATHIONE transferase ,ENZYME inhibitors ,DRUG resistance ,ONCOLOGY ,PEPTIDE drugs ,FUNCTIONAL groups - Abstract
Context: The inhibition of glutathioneS-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 (compounds1and5, respectively) have been disclosed as GST inhibitors. The rationale of their design is discussed in juxtaposition to non-peptide NBD thioethers. Materials and methods: Synthesis of derivatives1and5andin vitroevaluation on human GSTP1-1 and M2-2 are reported. Results: Conjugates1and5were 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). Discussion and conclusions: Spectroscopic data are congruent with the formation of a stable sigma-complex between GSH and the inhibitors in the protein active site. Conjugate5is suitable forin vivomodulation of GST activity in cancer treatment. [ABSTRACT FROM PUBLISHER]
- Published
- 2016
- Full Text
- View/download PDF