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  3. Structure guided design and synthesis of furyl thiazolidinedione derivatives as inhibitors of GLUT 1 and GLUT 4, and evaluation of their anti-leukemic potential

Structure guided design and synthesis of furyl thiazolidinedione derivatives as inhibitors of GLUT 1 and GLUT 4, and evaluation of their anti-leukemic potential

  • Eur J Med Chem. 2020 Sep 15;202:112603. doi: 10.1016/j.ejmech.2020.112603.
Kalpana Tilekar 1,  Neha Upadhyay 1,  Jessica D Hess 2,  Lucasantiago Henze Macias 2,  Piotr Mrowka 3,  Renato J Aguilera 2,  Franz-Josef Meyer-Almes 4,  Cristina V Iancu 5,  Jun-Yong Choe 6,  C S Ramaa 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, Maharashtra, India.
  • 2 The Cytometry, Screening and Imaging Core Facility & Border Biomedical Research Center & Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA.
  • 3 Department of Biophysics and Human Physiology, Medical University of Warsaw, Chalubinskiego, Warsaw, Poland.
  • 4 Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Darmstadt, Germany.
  • 5 East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, NC, USA.
  • 6 East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, NC, USA; Department of Biochemistry and Molecular Biology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA. Electronic address: choej18@ecu.edu.
  • 7 Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, Maharashtra, India. Electronic address: sinharamaa@yahoo.in.
PMID: 32634629 DOI: 10.1016/j.ejmech.2020.112603
Abstract

Cancer cells increase their glucose uptake and glycolytic activity to meet the high energy requirements of proliferation. Glucose transporters (GLUTs), which facilitate the transport of glucose and related hexoses across the cell membrane, play a vital role in tumor cell survival and are overexpressed in various cancers. GLUT1, the most overexpressed GLUT in many cancers, is emerging as a promising anti-cancer target. To develop GLUT1 inhibitors, we rationally designed, synthesized, structurally characterized, and biologically evaluated in-vitro and in-vivo a novel series of furyl-2-methylene thiazolidinediones (TZDs). Among 25 TZDs tested, F18 and F19 inhibited GLUT1 most potently (IC50 11.4 and 14.7 μM, respectively). F18 was equally selective for GLUT4 (IC50 6.8 μM), while F19 was specific for GLUT1 (IC50 152 μM in GLUT4). In-silico ligand docking studies showed that F18 interacted with conserved residues in GLUT1 and GLUT4, while F19 had slightly different interactions with the transporters. In in-vitro antiproliferative screening of leukemic/lymphoid cells, F18 was most lethal to CEM cells (CC50 of 1.7 μM). Flow cytometry analysis indicated that F18 arrested cell cycle growth in the subG0-G1 phase and lead to cell death due to necrosis and Apoptosis. Western blot analysis exhibited alterations in cell signaling proteins, consistent with cell growth arrest and death. In-vivo xenograft study in a CEM model showed that F18 impaired tumor growth significantly.

Keywords

Antiproliferative; Cytotoxicity; Furan; GLUT1; GLUT4; GLUT5; Inhibitor specificity; Leukemia; Thiazolidinedione (TZD).

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