2. Academic Validation
  3. New chromone derivatives bearing thiazolidine-2,4-dione moiety as potent PTP1B inhibitors: Synthesis and biological activity evaluation

New chromone derivatives bearing thiazolidine-2,4-dione moiety as potent PTP1B inhibitors: Synthesis and biological activity evaluation

  • Bioorg Chem. 2024 Feb:143:106985. doi: 10.1016/j.bioorg.2023.106985.
Yingying Zheng 1,  Li Lu 1,  Mengyue Li 1,  DeHua Xu 2,  LaiShun Zhang 3,  Zhuang Xiong 1,  Yubo Zhou 4,  Jia Li 4,  Xuetao Xu 5,  Kun Zhang 6,  Lei Xu 7
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, PR China.
  • 2 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 529199, PR China; School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, PR China.
  • 3 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 529199, PR China; School of Pharmacy, Zunyi Medical University, Zunyi 563006, PR China.
  • 4 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 529199, PR China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
  • 5 Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, PR China. Electronic address: [email protected].
  • 6 Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, PR China. Electronic address: [email protected].
  • 7 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 529199, PR China. Electronic address: [email protected].
PMID: 38007892 DOI: 10.1016/j.bioorg.2023.106985
Abstract

A series of chromone derivatives bearing thiazolidine-2,4-dione moiety (5 ∼ 37) were synthesized and evaluated for their PTP1B inhibitory activity, interaction analysis and effects on Insulin pathway in palmitic acid (PA)-induced HepG2 cells. The results showed that all derivatives presented potential PTP1B inhibitory activity with IC50 values of 1.40 ± 0.04 ∼ 16.83 ± 0.54 μM comparing to that of positive control lithocholic acid (IC50: 9.62 ± 0.14 μM). Among them, compound 9 had the strongest PTP1B inhibitory activity with the IC50 value of 1.40 ± 0.04 μM. Inhibition kinetic study revealed that compound 9 was a reversible mixed-type inhibitor against PTP1B. CD spectra results confirmed that compound 9 changed the secondary structure of PTP1B by their interaction. Molecular docking explained the detailed binding between compound 9 and PTP1B. Compound 9 also showed 19-fold of selectivity for PTP1B over TCPTP. Moreover compound 9 could recovery PA-induced Insulin resistance by increasing the phosphorylation of IRSI and Akt. CETSA results showed that compound 9 significantly increased the thermal stability of PTP1B.

Keywords

Chromone; Inhibitors; Protein tyrosine phosphatase 1B; Thiazolidine-2,4-dione.

Figures
Products