Di Micco Simone, Terracciano Stefania, Ruggiero Dafne, Potenza Marianna, Vaccaro Maria C, Fischer Katrin, Werz Oliver, Bruno Ines, Bifulco Giuseppe
European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy.
Dipartimento di Farmacia, University degli Studi di Salerno, Fisciano, Italy.
Front Chem. 2021 May 7;9:676631. doi: 10.3389/fchem.2021.676631. eCollection 2021.
We report the implementation of our /synthesis pipeline by targeting the glutathione-dependent enzyme mPGES-1, a valuable macromolecular target in both cancer therapy and inflammation therapy. Specifically, by using a virtual fragment screening approach of aromatic bromides, straightforwardly modifiable by the Suzuki-Miyaura reaction, we identified 3-phenylpropanoic acid and 2-(thiophen-2-yl)acetic acid to be suitable chemical platforms to develop tighter mPGES-1 inhibitors. Among these, compounds and showed selective inhibitory activity against mPGES-1 in the low micromolar range in accordance with molecular modeling calculations. Moreover, and exhibited interesting IC values on A549 cell lines compared to CAY10526, selected as reference compound. The most promising compound induced the cycle arrest in the G/G phase at 24 h of exposure, whereas at 48 and 72 h, it caused an increase of subG/G fraction, suggesting an apoptosis/necrosis effect.
我们报告了针对谷胱甘肽依赖性酶mPGES-1实施我们的合成管道，mPGES-1是癌症治疗和炎症治疗中一个有价值的大分子靶点。具体而言，通过使用芳基溴化物的虚拟片段筛选方法（可通过铃木-宫浦反应直接修饰），我们确定3-苯基丙酸和2-(噻吩-2-基)乙酸是开发更紧密的mPGES-1抑制剂的合适化学平台。其中，化合物 和 在低微摩尔范围内对mPGES-1表现出选择性抑制活性，这与分子建模计算结果一致。此外，与选为参考化合物的CAY10526相比，化合物 和 在A549细胞系上表现出有趣的IC值。最有前景的化合物 在暴露24小时时诱导细胞周期停滞在G/G期，而在48小时和72小时时，它导致亚G/G分数增加，表明有凋亡/坏死效应。
