谷氨酰胺代谢是几种癌症的重要标志,在胶质母细胞瘤癌细胞(GBM)中具有证明的抗肿瘤活性。GBM细胞通过谷氨酰胺分解过程调节谷氨酰胺并将其用作其增殖的主要能量来源。酶,例如谷氨酰胺分解中的谷氨酰胺酶,可以被小分子抑制剂靶向,从而显示出有希望的抗癌特性。对谷氨酰胺分解的抗性需要开发新的治疗分子来克服耐药性。在这里,我们已经报道了一个新的限制甲基苯并[b,f][1,5]二氧辛衍生物作为谷氨酰胺酶(GLS)抑制剂及其抗GBM潜力。通过2'-羟基苯乙酮的自缩合获得由七个分子组成的文库,其中三个分子,即化合物3、5和6用GLS(PDBID;4O7D)鉴定为具有范围在-10.2和-9.8kcal/mol之间的更高的结合能值。这些化合物的药理学验证在GBM细胞中也显示出比标准药物替莫唑胺(TMZ)更高的生长抑制作用。最有前途的化合物,6,遵守Lipinski的5条规则,并被鉴定与GLS的关键残基Arg307,Asp326,Lys328,Lys399和Glu403相互作用。该化合物在LN229和SNB19细胞中表现出最佳的细胞毒性作用,IC50值为63μM和83μM,分别。最佳约束二苯并[b,f][1,5]dioxocininthetestedseriesincreasedprotocoatingviareactiveoxygenspeciesproductioninbothGBMcells,并随着时间的推移在两种细胞系中均表现出抗迁移和抗增殖特性。我们的结果强调了二苯并[b,f][1,5]dioxocin从结构的基础上,并证明谷氨酰胺分解的抑制可能有助于GBM治疗的药理学干预。
Glutamine metabolism is an important hallmark of several cancers with demonstrated antitumor activity in glioblastoma cancer cells (GBM). GBM cells regulate glutamine and use it as a major energy source for their proliferation through the glutaminolysis process. Enzymes, such as glutaminase in glutaminolysis, can be targeted by small-molecule inhibitors, thus exhibiting promising anticancer properties. The resistance to glutaminolysis demands the development of new therapeutic molecules to overcome drug resistance. Herein, we have reported a novel library of constrained methanodibenzo[b,f][1,5]dioxocin derivatives as glutaminase (GLS) inhibitors and their anti-GBM potential. The library consisting of seven molecules was obtained through self-condensation of 2\'-hydroxyacetophenones, out of which three molecules, namely compounds 3, 5, and 6, were identified with higher binding energy values ranging between -10.2 and -9.8 kcal/mol with GLS (PDB ID; 4O7D). Pharmacological validation of these compounds also showed a higher growth inhibition effect in GBM cells than the standard drug temozolomide (TMZ). The most promising compound, 6, obeyed Lipinski\'s rule of five and was identified to interact with key residues Arg307, Asp326, Lys328, Lys399, and Glu403 of GLS. This compound exhibited the best cytotoxic effect with IC50 values of 63 µM and 83 µM in LN229 and SNB19 cells, respectively. The potential activation of GLS by the best-constrained dibenzo[b,f][1,5]dioxocin in the tested series increased apoptosis via reactive oxygen species production in both GBM cells, and exhibited anti-migratory and anti-proliferative properties over time in both cell lines. Our results highlight the activation mechanism of a dibenzo[b,f][1,5]dioxocin from the structural basis and demonstrate that inhibition of glutaminolysis may facilitate the pharmacological intervention for GBM treatment.