a Department of Pharmacy , "Gabriele d'Annunzio" University , Chieti , Italy .
b Department of Drug Chemistry and Technologies , "Sapienza" University , Rome , Italy .
J Enzyme Inhib Med Chem. 2016 Dec;31(6):924-30. doi: 10.3109/14756366.2015.1070845. Epub 2015 Sep 2.
The inhibition of glutathione S-transferase P1-1 (GSTP1-1) is a sound strategy to overcome drug resistance in oncology practice.
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.
Synthesis of derivatives 1 and 5 and in vitro evaluation on human GSTP1-1 and M2-2 are reported.
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).
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.
抑制谷胱甘肽 S-转移酶 P1-1（GSTP1-1）是克服肿瘤学实践中耐药性的合理策略。
谷胱甘肽的硝基金属苯并二唑基（NBD）S-轭合物和相应的γ-氧代-谷氨酸同系物（分别为化合物 1 和 5）已被披露为 GST 抑制剂。讨论了其设计的原理，并与非肽 NBD 硫醚并列。
报告了衍生物 1 和 5 的合成及其对人 GSTP1-1 和 M2-2 的体外评估。
发现共轭物 1 和 5 是两种同工酶的低微摩尔抑制剂。此外，与强效非肽抑制剂硝基金属苯并二唑基-硫代己醇（NBDHEX）相比，它们对 GSTM2-2 的选择性降低了三倍，对 P1-1 同工酶的选择性降低了三倍。
光谱数据与抑制剂在蛋白质活性部位与 GSH 形成稳定的 σ-配合物一致。共轭物 5 适合在癌症治疗中体内调节 GST 活性。
