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

Reddy, D RajasekharDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States (author)

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.

Ballante, FlavioDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States(Swepub:uu)flaba767 (author)
Zhou, Nancy JDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States (author)
Marshall, Garland RDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States (author)
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States (creator_code:org_t)

In:European Journal of Medicinal Chemistry: Elsevier BV127, s. 531-5530223-52341768-3254

By the author/editor: Reddy, D Rajasek ...; Ballante, Flavio; Zhou, Nancy J; Marshall, Garlan ...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medicinal Chemis ...

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