Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors

D. Rajasekhar Reddy, Flavio Ballante, Nancy J. Zhou, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

A comprehensive investigation was performed to identify new benzodiazepine (BZD) derivatives as potent and selective human lysine deacetylase inhibitors (hKDACis). A total of 108 BZD compounds were designed, synthesized and from that 104 compounds were biologically evaluated against human lysine deacetylases (hKDACs) 1, 3 and 8 (class I) and 6 (class IIb). The most active compounds showed mid-nanomolar potencies against hKDACs 1, 3 and 6 and micromolar activity against hKDAC8, while a promising compound (6q) showed selectivity towards hKDAC3 among the different enzyme isoforms. An hKDAC6 homology model, refined by molecular dynamics simulation was generated, and molecular docking studies performed to rationalize the dominant ligand-residue interactions as well as to define structure-activity-relationships. Experimental results confirmed the usefulness of the benzodiazepine moiety as capping group when pursuing hKDAC isoform-selectivity inhibition, suggesting its continued use when designing new hKDACis.

Original languageEnglish
Pages (from-to)531-553
Number of pages23
JournalEuropean Journal of Medicinal Chemistry
Volume127
DOIs
StatePublished - 2017

Keywords

  • Benzodiazepine (BZD)
  • Epigenetics
  • Histone deacetylase (HDAC)
  • Lysine deacetylase (KDAC)
  • Structure-based drug design (SBDD)

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