Discovery and preliminary evaluation of 2-aminobenzamide and hydroxamate derivatives containing 1,2,4-oxadiazole moiety as potent histone deacetylase inhibitors

Jin Cai, Hongtao Wei, Kwon Ho Hong, Xiaoqing Wu, Meng Cao, Xi Zong, Lushen Li, Chunlong Sun, Junqing Chen, Min Ji

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Using Entinostat as a lead compound, 2-aminobenzamide and hydroxamate derivatives have been designed and synthesized. The entire target compounds were investigated for their in vitro antiproliferative activities using the MTT-based assay against five human cancer cell lines including U937, A549, NCI-H661, MDA-MB-231 and HCT116. 2-Aminobenzamide series of compounds (10a-10j) demonstrated the most significant inhibition against human acute monocytic myeloid leukemia cell line U937, but no or poor activities against two human lung cancer cell lines. Furthermore, the target compounds were screened for their inhibitory activities against HDAC 1, 2, and 8. 2-Aminobenzamide derivatives (10) manifested a higher selectivity for HDAC 1 over HDAC 2, but were not active against HDAC 8. In contrast, most hydroxamate derivatives (11) inhibit HDAC 8 with lower IC50 values than SAHA and Entinostat. Docking study with selected compounds 10f and 11a revealed that the compounds might bind tightly to the binding pockets in HDAC 2 and HDAC 8, respectively. The results suggest that they may be promising lead compounds for the development of novel anti-tumor drug potentially via inhibiting HDACs.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume96
DOIs
StatePublished - May 26 2015

Keywords

  • 2-Aminobenzamide
  • Antiproliferative activity
  • Cancer cell
  • Docking simulation
  • Histone deacetylases
  • Hydroxamate

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