title: Inhibitors of human histone deacetylase: synthesis and enzyme assay of hydroxamates with piperazine linker.
abstract: The histone deacetylase (HDAC) enzyme plays an important role in gene transcription. Inhibitors of histone deacetylases induce cell differentiation and suppress cell proliferation in tumor cells. Hydroxamates with rigid linker have displayed better inhibition profiles than those with linear and flexible aliphatic linkers. We have designed and synthesized several potential histone deacetylase inhibitors with a piperazine moiety in the linker region to test the effect of reduced linker flexibility. Inhibitors were evaluated for their inhibitory action on human HDAC3/NCoR2 and HDAC8. N-Hydroxycarboxamide derivatives (compounds 4a-d) were found to be better than N-hydroxyacetamide derivatives (compounds 6a-d) against HDAC8. Amongst the synthesized compounds, 4a (HDAC8, IC50: 3.15 microM) with no substitution in the aryl cap was the most active and promising lead for further investigations.
authors.affiliation: Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.
authors.forename: Shubhashis
authors.initials: S
authors.lastname: Chakrabarty
authors.lastname: Jasmine
authors.forename: Chetan
authors.initials: C
authors.lastname: Bhadaliya
authors.forename: Barij Nayan
authors.initials: BN
authors.lastname: Sinha
authors.forename: Aruna
authors.initials: A
authors.lastname: Mahesh
authors.forename: He
authors.initials: H
authors.lastname: Bai
authors.forename: Sylvie Y
authors.initials: SY
authors.lastname: Blond
authors.forename: Venkatesan
authors.initials: V
authors.lastname: Jayaprakash
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D004353:Drug Evaluation, Preclinical; D057075:Enzyme Assays / Q000379:methods*; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010879:Piperazines