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

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, K-562, 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 (IC 50-9.3 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 (IC 50-28.2 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 (CC 50-104.2 μM) and human fibroblasts (HS27) (CC 50-105.0 μM). Thus, among this novel series of TZD *

HDAC4 Inhibitors with Cyclic Linker and Non‐hydroxamate Zinc Binding Group: Design, Synthesis, HDAC Screening and in vitro Cytotoxicity evaluation.

“…Designing of the molecules N-substituted pyridyl TZD analogs were previously described to be generally inactive against HDAC4, but some structures from this series showed moderate activity against another HDAC isoenzyme, HDAC8. As an example, P19 has an IC 50 -value of 9.3 μM [22] (Figure 2). Docking results suggest that P19 binds the zinc ion at the bottom of the canonical binding site through its carbonyl oxygen and occupies the lower side of the pocket that connects the active site with the acetate release channel.…”

“…Optimization of dual activity of TZD analogs against HDAC4 and HDAC8. P19 is a moderate HDAC8 selective inhibitor, [22] 3k shows improved activity on both, HDAC4 and HDAC8, [28] and 5w shows selectivity for HDAC4. binding TZD group shows also T-shaped PiÀ Pi interactions with the imidazole ring of His198.…”

“…In search of non‐hydroxamate HDAC inhibitors, we have recently reported thiazolidinedione (TZD) containing structurally diverse selective HDAC8 and dual HDAC4/8 inhibitors with good to moderate potency. In the present work we have attempted the hybridization/ permutation of these reported series with the aim to optimize our previously reported TZD containing molecules [22] and develop more potent and selective HDAC4 inhibitors with anticancer potential in various cancer cell lines.…”

Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine‐2,5‐dione Hybrids as Potential Antitumor Agents

“…The intriguing cytotoxic/antiproliferative effects in various tumor cells shown by both pyrrolidine‐2,5‐dione‐ and pyrazoline‐based derivatives prompted us to investigate the activity of S1 – S13 in solid and hematological tumor cell lines. In vitro cytotoxicity of the compounds was determined by MTT assay utilizing three cell lines, myeloid leukemia cell line K562, breast cancer cell line MCF7, and colon cancer cell line HT29, as described previously . Each cell line was exposed to test compounds for 48 h. Paclitaxel and pioglitazone were used as standard references and untreated cells were used as negative control.…”

“…In vitro cytotoxicity of the compounds was determined by MTT assay utilizing three cell lines, myeloid leukemia cell line K562, breast cancer cell line MCF7, and colon cancer cell line HT29, as described previously. [41,42] Each cell line was exposed to test compounds for 48 h. Paclitaxel and pioglitazone were used as standard references and untreated cells were used as negative control. Paclitaxel was selected as one of the standards as it is a clinically used anticancer agent, whereas pioglitazone was chosen as second standard as it is a PPARγ agonist containing the TZD group bio-isostere of pyrrolidine-2,5-dione.…”