A hybrid of thiazolidinone with the hydroxamate scaffold for developing novel histone deacetylase inhibitors with antitumor activities

Abstract

A series of novel histone deacetylase (HDAC) inhibitors were designed, synthesized and evaluated based on the strategies of a hybrid of the classic pharmacophore of HDAC inhibitors with the thiazolidinone scaffold. Some of the compounds 12i showed potent HDAC1 inhibition with nM IC50 values, more importantly, compound displayed much better anti-metastatic effects than vorinostat (SAHA) against migration of the A549 cell line. Further mechanism exploration implied that compound 12i may inhibit tumor metastasis via modulating the epithelial-mesenchymal transition (EMT) and upregulating the acetylation of α-tubulin.

Synthesis and in vitro antibacterial, antifungal, anti-proliferative activities of novel adamantane-containing thiazole compounds

“…The PASS analysis results indicated that the predicted highest probability of biological activity (Pa) was for histone deacetylase (HDAC) SIRT1 enzyme (Table S2 ). The PASS prediction results are supported by the reported HDAC inhibitory activity of various adamantane 52 – 54 and thiazole 28 , 29 , 55 – 59 derivatives.…”

Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

“…Valproic acid (VPA) and sodium phenylbutyrate are two representative compounds of this class, and they are still under investigation for their anticancer efficacies in clinical trials 125 . Our laboratory has discovered a new series of novel hydroxamate‐based HDAC inhibitors with significant antitumor effects and these compounds significantly suppresses the growth and metastasis of some solid tumors in mouse models 126–129 . Further research found that this type of HDACIs has a potent sensitizing effect on non‐small cell lung cancer (NSCLC) that is counteractive to the EGFR TKI drug erlotinib, and thus restored the therapeutic effect of erlotinib in NSCLC 130 .…”

“…125 Our laboratory has discovered a new series of novel hydroxamate-based HDAC inhibitors with significant antitumor effects and these compounds significantly suppresses the growth and metastasis of some solid tumors in mouse models. [126][127][128][129] Further research found that this type of HDACIs has a potent sensitizing effect on non-small cell lung cancer (NSCLC) that is counteractive to the EGFR TKI drug erlotinib, and thus restored the therapeutic effect of erlotinib in NSCLC. 130 Moreover, the subsequently optimized lead compound showed great potential in preclinical studies of BC.…”

A novel benzamine lead compound of histone deacetylase inhibitor ZINC24469384 can suppresses HepG2 cells proliferation by upregulating NR1H4

“…HDACs were involved in condensing chromatin so can downregulating many genes expression, while HATs can removes the positive charge on the histones, so the chromatin can transform to a more open structures and active the transcription. In recently study global hypoacetylation of histone is also correlated with numerous specific processes like the occurrence and development of tumor, with the features of uncontrolled cell growth, proliferation and so on 1,2 . Now, 11 classical human HDACs have been identified and grouped into three Classes based on their sequence homology to yeast orthologues Rpd3, Hdal and Sir2, respectively 3 .…”