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.
Neha Upadhyay  1 ,  Kalpana Tilekar  1 ,  Niklas Jänsch  2 ,  Markus Schweipert  2 ,  Jessica D Hess  3 ,  Luca Henze Macias  3 ,  Piotr Mrowka  4 ,  Renato J Aguilera  3 ,  Jun-Yong Choe  5 ,  Franz-Josef Meyer-Almes  6 ,  C S Ramaa  7
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, India.
  • 2. Department of Chemical Engineering and Biotechnology, University of Applied Science, Darmstadt, Germany.
  • 3. The Cellular Characterization and Biorepository Core Facility & Border Biomedical Research Centre & Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA.
  • 4. Department of Biophysics and Human Physiology, Medical University of Warsaw, Chalubinskiego, Warsaw, Poland; Institute of Hematology and Blood Transfusion, Indira Gandhi St., Warsaw, Poland.
  • 5. East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA; Department of Biochemistry and Molecular Biology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
  • 6. Department of Chemical Engineering and Biotechnology, University of Applied Science, Darmstadt, Germany. Electronic address: [email protected].
  • 7. Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, India. Electronic address: [email protected].
PMID: 32446120 DOI: 10.1016/j.bioorg.2020.103934
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.
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