Hou Wei, Zhou Yucheng, Rui Jingjing, Bai Ruisong, Bhasin Aman K K, Ruan Benfang Helen
College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology (IDD &CB), Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China.
Department of Chemistry and Centre of Advanced Sciences, Panjab University, Sector 14, Chandigarh 160014, India.
Bioorg Med Chem Lett. 2019 Jul 1;29(13):1673-1676. doi: 10.1016/j.bmcl.2019.04.032. Epub 2019 Apr 24.
Organotellurium compounds have been reported as an immune-modulator sensitizing chemotherapeutics. Herein, we report the design and synthesis of a series of novel tellurodibenzoic acids as mimics of diphenylarsenic acid (DPAA) and potential selective KGA inhibitors. Representative compound 3B exhibited potent inhibition of KGA and glutamine-dependent HCT-116 cells. Stability experiments indicated that 3B has excellent stability under acidic (HCOOH), basic (NH·HO) and oxidative (HO) conditions, but reacts with β-ME, DTT and lysine which suggested that compound 3B may interact with cysteine or lysine residues. Moreover, molecular docking disclosed that compound 3B binds to the allosteric site of the GAC tetramer containing Arg-Lys-Leu-Phe-Tyr-Glu, which helped to rationalize the SAR and further design and optimization. Taken together, compound 3B could be used as a starting point for the development of new KGA inhibitors.
有机碲化合物已被报道为一种使化疗药物敏感的免疫调节剂。在此，我们报告了一系列新型碲二苯甲酸的设计与合成，它们是二苯基砷酸（DPAA）的类似物以及潜在的选择性KGA抑制剂。代表性化合物3B对KGA和谷氨酰胺依赖性HCT - 116细胞表现出强效抑制作用。稳定性实验表明，3B在酸性（HCOOH）、碱性（NH·HO）和氧化（HO）条件下具有出色的稳定性，但会与β - ME、DTT和赖氨酸发生反应，这表明化合物3B可能与半胱氨酸或赖氨酸残基相互作用。此外，分子对接显示化合物3B与含有Arg - Lys - Leu - Phe - Tyr - Glu的GAC四聚体的变构位点结合，这有助于合理化构效关系并进行进一步的设计和优化。综上所述，化合物3B可作为开发新型KGA抑制剂的起点。
