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Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.ORCID iD: 0000-0002-4831-3423
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
2017 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 127, 531-553 p., S0223-5234(16)31038-8Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 127, 531-553 p., S0223-5234(16)31038-8
Keyword [en]
Benzodiazepine (BZD), Epigenetics, Histone deacetylase (HDAC), Lysine deacetylase (KDAC), Structure-based drug design (SBDD)
National Category
Medicinal Chemistry Biological Sciences Chemical Sciences Computer and Information Science
Identifiers
URN: urn:nbn:se:uu:diva-321297DOI: 10.1016/j.ejmech.2016.12.032PubMedID: 28109947OAI: oai:DiVA.org:uu-321297DiVA: diva2:1095267
Available from: 2017-05-12 Created: 2017-05-12 Last updated: 2017-05-12

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