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

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

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

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

Neha Upadhyay et al. Bioorg Chem. 2020 Jul.

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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Conflict of interest statement

Declaration of Competing Interest None.

Figures

Figure 1.
Figure 1.
Reported selective HDAC8 inhibitors: PCI34051 (1), linkerless hydroxamic acid (2), ortho-aryl N-hydroxycinnamide (3), NCC149 (4), azetidinone (5) [–16].
Figure 2.
Figure 2.
Designing aspects of novel HDAC8 inhibitors [11,13,14,23].
Figure 3.
Figure 3.. Screening of P1-P25 on two different classes of HDAC isoforms, HDAC4 and HDAC8.
Primary screening of all target compounds at 50 μM against HDAC4 (A) and HDAC8 (B). (C) Dose response curves of P5, P9, P10, P12, and P19 on HDAC4. (D) Dose response curves of P5, P9, P10, P12, and P19 on HDAC8.
Figure 4.
Figure 4.
Dose response curve of P10 and P19 on different HDAC isoforms.
Figure 5.
Figure 5.. Effect of the test compounds on the relative transport activity of GLUT 1, 4, and 5.
Percent relative activity of GLUT1 (A), GLUT4 (C), and GLUT5 (D) in the presence of 50 μM concentration of test compound. (B) Dose response curve of P19 in GLUT1. Transport assay was initiated by the addition of 5 mM C14-glucose (for GLUT1 and GLUT4) or 10 mM C14- fructose (GLUT5) to hxt0 yeast cells expressing GLUT1, GLUT4, or GLUT5 (see Material and Methods for details). The transport activity was measured in triplicates and means with S.D. are shown.
Figure 6.
Figure 6.. Analysis of apoptosis induced by compounds P10 and P19 on CEM cells.
(A-B) Cytograms of test compounds P10 and P19, respectively. CEM cells were treated with IC50 concentration of compounds P10 (A) and compound P19 (B) for 24 h. (C) Graphical representation of apoptotic events of control (1% DMSO), P10-treated and P19-treated cells.
Figure 7.
Figure 7.
Docking analysis of compound P19 on HDAC8 (PDB ID 1T69) and HDAC4 (PDB ID 2VQJ). A) 3D binding pose of P19 (stick-and-ball model) within the binding pocket of HDAC8. B) 2D ligand interactions between P19 and HDAC8. Hydrogen bonds are indicated by dashed green lines (A) or dotted green or blue arrows (B) and metal ion contacts are shown as dotted magenta lines. C) Superposition of docking poses of P19 in the binding pocket of HDAC8 (PDB ID 1T69, orange) and HDAC4 (PDB ID 2VQJ, magenta). Green spheres represent the catalytic zinc ion of both structures. The amino acids are annotated according to the respective PDB file. The meshed surfaces indicate the respective binding pocket surfaces of HDAC8 (orange) and HDAC4 (magenta).
Scheme 1.
Scheme 1.. Synthetic route of P1-P25.
Reaction conditions: a) DCM, K2CO3, 0 0C, stirring; b) AcOH, Sodium acetate, reflux 5 h; c) EtOH, KOH, reflux 3 h; d) Methanol, reflux 6 h.
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