Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Bioorg Chem. 2020 Jul:100:103934. doi: 10.1016/j.bioorg.2020.103934. Epub 2020 May 15.

Abstract

Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC50 - 9.3 μM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC50 - 28.2 μM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC50 - 104.2 μM) and human fibroblasts (HS27) (CC50 - 105.0 μM). Thus, among this novel series of TZD derivatives, compound P19 was most promising HDAC8 inhibitor and cytotoxic on leukemic cells. Thus, P19 could serve as a lead for further development of optimized molecules with enhanced selectivity and potency.

Keywords: Docking; GLUT; HDAC; Leukemia; N-substituted thiazolidinediones.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / drug effects
  • Binding Sites
  • Cell Line
  • Cell Survival / drug effects
  • Drug Evaluation, Preclinical
  • Glucose Transporter Type 1 / antagonists & inhibitors
  • Glucose Transporter Type 1 / metabolism
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / metabolism*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism
  • Humans
  • Molecular Docking Simulation
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / metabolism
  • Structure-Activity Relationship
  • Thiazolidinediones / chemistry*
  • Thiazolidinediones / metabolism
  • Thiazolidinediones / pharmacology

Substances

  • Glucose Transporter Type 1
  • Histone Deacetylase Inhibitors
  • Protein Isoforms
  • Repressor Proteins
  • Thiazolidinediones
  • HDAC8 protein, human
  • Histone Deacetylases