title: 2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity.
abstract: We have screened our compound collection in an established cell based assay that measures the derepression of an epigenetically silenced transgene, the locus derepression assay. The screen led to the identification of 4-[4-(1-methylbenzimidazol-2-yl)piperazin-1-yl]sulfonylbenzenecarbohydroxamic acid (9b) as an active which was found to inhibit HDAC1. In initial structure activity relationships study, the 1-methylbenzimidazole ring was replaced by the isosteric heterocycles benzimidazole, benzoxazole, and benzothiazole and the position of the hydroxamic acid substituent on the phenyl ring was varied. Whereas compounds bearing a para substituted hydroxamic acid (9a-d) were active HDAC inhibitors, the meta substituted analogues (8a-d) were appreciably inactive. Compounds 9a-d selectively inhibited HDAC6 (IC50 = 0.1-1.0 μM) over HDAC1 (IC50 = 0.9-6 μM) and moreover, also selectively inhibited the growth of lung cancer cells vs. patient matched normal cells. The compounds induce a cell cycle arrest in the S-phase while induction of apoptosis is neglible as compared to controls. Molecular modeling studies uncovered that the MM-GBSA energy for interaction of 9a-d with HDAC6 was higher than for HDAC1 providing structural rationale for the HDAC6 selectivity.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Chemistry, Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
authors.forename: Marina
authors.initials: M
authors.lastname: Kofler
authors.affiliation: Division of Molecular Biology, Center for Chemistry and Biomedicine, Innsbruck Medical University Innrain 80-82, A-6020 Innsbruck Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Brosch
authors.affiliation: Institute of Pharmacy, Department of Medicinal Chemistry, Martin-Luther-Universität Halle-Wittenberg, D-06099 Halle/Saale, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Melesina
authors.affiliation: Institute of Pharmacy, Department of Medicinal Chemistry, Martin-Luther-Universität Halle-Wittenberg, D-06099 Halle/Saale, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, United States of America.|Department of Pharmacology, UT Southwestern Medical center, Dallas, TX, United States of America.
authors.forename: Elisabeth D
authors.initials: ED
authors.lastname: Martinez
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Chemistry, Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
authors.forename: Johnny
authors.initials: J
authors.lastname: Easmon
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C000608941:4-(4-(1-methylbenzimidazol-2-yl)piperazin-1-yl)sulfonylbenzenecarbohydroxamic acid; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D006655:Histone Deacetylases