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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, 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.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Upadhyay N,Tilekar K,Jänsch N,Schweipert M,Hess JD,Henze Macias L,Mrowka P,Aguilera RJ,Choe JY,Meyer-Almes FJ,Ramaa CS

doi

10.1016/j.bioorg.2020.103934

subject

Has Abstract

pub_date

2020-07-01 00:00:00

pages

103934

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(20)30740-9

journal_volume

100

pub_type

杂志文章

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