title: Optimization of histone deacetylase inhibitor activity in non-secosteroidal vitamin D-receptor agonist hybrids.
abstract: The combination of (1α,25)-dihydroxyvitamin D3 (1,25D) and histone deacetylase inhibitor (HDACi) trichostatin A is highly antiproliferative in numerous cancer cell lines. We have previously prepared novel non-secosteroidal hybrid molecules which simultaneously act as both vitamin D receptor (VDR) agonists and HDACi. These molecules function as cytostatic and cytotoxic agents in 1,25D-resistant SCC4 squamous carcinoma cells. Here we have extended the scope of the hybrids by making several modifications to the diarylpentane core and to the aliphatic spacer unit to develop molecules with increased potency towards HDACs while maintaining VDR agonist activity. Notably, hybrid DK-366 (33a), a direct analog of first-generation hybrids but lacking a methyl group on one aryl ring possesses low micromolar potency for HDAC3 and HDAC6 and is a highly effective antiproliferative agent in SCC4 cells. Chain extended hybrids such as DK-367 (33c) possess even greater HDAC potency and are also highly antiproliferative. These results show that we can optimize HDACi potency in hybrid molecules without sacrificing VDR agonism.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, Quebec H3A 0B8, Canada.
authors.forename: Dainis
authors.initials: D
authors.lastname: Kaldre
authors.affiliation: Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Québec H3G 1Y6, Canada.
authors.forename: Tian-Tian
authors.initials: TT
authors.lastname: Wang
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, Quebec H3A 0B8, Canada.
authors.forename: Joshua
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Québec H3G 1Y6, Canada; Department of Medicine, McGill University, 3655 Promenade Sir William Osler, Montreal, Québec H3G 1Y6, Canada. Electronic address: john.white@mcgill.ca.
authors.forename: John H
authors.initials: JH
authors.lastname: White
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, Quebec H3A 0B8, Canada. Electronic address: jim.gleason@mcgill.ca.
authors.forename: James L
authors.initials: JL
authors.lastname: Gleason
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D054697:Cytostatic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018167:Receptors, Calcitriol; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; C012589:trichostatin A; D006655:Histone Deacetylases
keywords: Cancer; Histone deacetylase; Hybrids; Vitamin D