Targeting G6PD with Benzimidazole and Thiazole Derivatives Suppresses SIRT 2 and VEGF Expression and Induces Cytotoxicity in Glioma Cells.

Hypoxia and activation of the pentose phosphate pathway (PPP), as well as overexpression of glucose-6-phosphate dehydrogenase (G6PD), are hallmark features of glioblastomas (GBM), contributing significantly to tumor progression metabolic adaptation and drug resistance. This study aimed to evaluate the cytotoxic effects of nine synthetic compounds incorporating annulated benzimidazole and nitrothiazole scaffolds in two glioblastoma cell lines (A172 and U87-MG) under both normoxic and hypoxic conditions. Three compounds (BZM-7, BZM-9, and CNZ-3) demonstrated potent anticancer activity, with CNZ-3 exhibiting the highest efficacy, particularly in hypoxia. The study further investigated the effects of these compounds on the expression of the G6PD gene, as well as post-translational regulatory genes SIRT2 and KAT9, and the angiogenesis-related VEGF gene. Transcriptional analyses showed that the nitrothiazole-derived compound CNZ-3 significantly downregulated G6PD, SIRT2, KAT9 and VEGF expression under hypoxic conditions, suggesting selective interference with hypoxia-adaptative pathways. In contrast, BZM-7 and BZM-9 showed distinct expression patterns, indicating diverse mechanisms of action despite structural similarity. In addition, BZM-7, BZM-9, and CNZ-3 were identified as potent inhibitors of recombinant G6PD, demonstrating both enzymatic inhibition and structural alterations, suggesting that G6PD could be a relevant therapeutic target for these compounds. Furthermore, molecular docking analysis revealed favorable binding interactions between the compounds and key amino acids of the G6PD, reinforcing their potential as a direct enzyme inhibitors. These findings highlight the pivotal role of G6PD in gliomas under hypoxic conditions and support its inhibition as a promising therapeutic strategy.