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  3. Biological evaluation and SAR analysis of novel covalent inhibitors against fructose-1,6-bisphosphatase

Biological evaluation and SAR analysis of novel covalent inhibitors against fructose-1,6-bisphosphatase

  • Bioorg Med Chem. 2020 Sep 15;28(18):115624. doi: 10.1016/j.bmc.2020.115624.
Xinya Han 1,  Yunyuan Huang 2,  Lin Wei 2,  Haifeng Chen 3,  Yanrong Guo 1,  Zilong Tang 4,  Wei Hu 1,  Qinfei Xia 1,  Qi Wang 1,  Jufen Yan 5,  Yanliang Ren 6
Affiliations

Affiliations

  • 1 School of Chemistry and Chemical Engineering, Anhui University of Technology, Maanshan 243002, China.
  • 2 International Cooperation Base of Pesticide and Green Synthesis (Hubei), Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University, Wuhan 430079, China.
  • 3 Ocean College, Beibu Gulf University, Qinzhou 535011, China.
  • 4 Key Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education, Hunan University of Science and Technology, Xiangtan 411201, China.
  • 5 School of Chemistry and Chemical Engineering, Anhui University of Technology, Maanshan 243002, China. Electronic address: yanjvfen@163.com.
  • 6 International Cooperation Base of Pesticide and Green Synthesis (Hubei), Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, Department of Chemistry, Central China Normal University, Wuhan 430079, China. Electronic address: renyl@mail.ccnu.edu.cn.
PMID: 32828433 DOI: 10.1016/j.bmc.2020.115624
Abstract

Fructose-1,6-bisphosphatase (FBPase) is an attractive target for affecting the GNG pathway. In our previous study, the C128 site of FBPase has been identified as a new allosteric site, where several nitrovinyl compounds can bind to inhibit FBPase activity. Herein, a series of nitrostyrene derivatives were further synthesized, and their inhibitory activities against FBPase were investigated in vitro. Most of the prepared nitrostyrene compounds exhibit potent FBPase inhibition (IC50 < 10 μM). Specifically, when the substituents of F, Cl, OCH3, CF3, OH, COOH, or 2-nitrovinyl were installed at the R2 (meta-) position of the benzene ring, the FBPase inhibitory activities of the resulting compounds increased 4.5-55 folds compared to those compounds with the same groups at the R1 (para-) position. In addition, the preferred substituents at the R3 position were Cl or Br, thus compound HS36 exhibited the most potent inhibitory activity (IC50 = 0.15 μM). The molecular docking and site-directed mutation suggest that C128 and N125 are essential for the binding of HS36 and FBPase, which is consistent with the C128-N125-S123 allosteric inhibition mechanism. The reaction enthalpy calculations show that the order of the reactions of compounds with thiol groups at the R3 position is Cl > H > CH3. CoMSIA analysis is consistent with our proposed binding mode. The effect of compounds HS12 and HS36 on glucose production in primary mouse hepatocytes were further evaluated, showing that the inhibition was 71% and 41% at 100 μM, respectively.

Keywords

Covalent inhibitors; FBPase inhibitors; Fructose-1,6-bisphosphatase (FBPase).

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