In:
New Journal of Chemistry, Royal Society of Chemistry (RSC), Vol. 47, No. 16 ( 2023), p. 7622-7631
Abstract:
Histone deacetylases (HDACs) have proven to be promising targets for the development of anticancer drugs. In this work, we report the design and synthesis of a series of 19 novel hydroxamic acid-based histone deacetylase inhibitors conjugated to benzimidazole and benzoxazole core structures. Five compounds showed anti-proliferative activity with an IC 50 value of 2.9–70.9 μM. Compound 7 displayed the highest efficacy against MCF-7 cells and exhibited antiproliferative effects against a panel of cancer cell lines. Compound 7 was the most potent selective inhibitor of HDAC6 and had an IC 50 value 8- to 〉 111.1-fold those of HDAC3, HDAC4, HDAC8, and HDAC11, and was a superior HDAC6 inhibitor to belinostat. Its interaction with and inhibitory activity on HDAC enzymes were then explored in a molecular docking study. The obtained data revealed the highest binding affinity (−8.46 kcal mol −1 ) of compound 7 toward HDAC6, as it formed interactions with the key residues Cys584 and Asp612 within the active site. Furthermore, the HDAC inhibitory activity of compound 7 was demonstrated from the dose-dependent increase in the tubulin acetylation level. Together, our results indicated that compound 7 with a cap of benzimidazole and four carbon-chain-containing thioether linker is a potent anticancer agent for selective HDAC6 inhibition and deserves further investigation.
Type of Medium:
Online Resource
ISSN:
1144-0546
,
1369-9261
Language:
English
Publisher:
Royal Society of Chemistry (RSC)
Publication Date:
2023
detail.hit.zdb_id:
1472933-7
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