title: Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes.
abstract: Inhibition of histone deacetylase (HDAC) enzymes has emerged as a target for development of cancer chemotherapy. Four compounds have gained approval for clinical use by the Food and Drug Administration in the US, and several are currently in clinical trials. However, none of these compounds possesses particularly good isozyme selectivity, which would be a highly desirable feature in a tool compound. Whether selective inhibition of individual HDAC isozymes will provide improved drug candidates remains to be seen. Nevertheless, it has been speculated that using macrocyclic compounds to target HDAC enzymes might hold an advantage over the use of traditional hydroxamic-acid-containing inhibitors, which rely on chelation to the conserved active-site zinc ion. Here we review the literature on macrocyclic HDAC inhibitors obtained from natural sources and on structure-activity relationship studies inspired by these molecules, as well as on efforts aimed at fully synthetic macrocyclic HDAC inhibitors.
authors.affiliation: Center for Biopharmaceuticals and, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Alex R
authors.identifier: http://orcid.org/0000-0002-1894-0821
authors.initials: AR
authors.lastname: Maolanon
authors.affiliation: Center for Biopharmaceuticals and, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Helle M E
authors.initials: HM
authors.lastname: Kristensen
authors.affiliation: Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Leman
authors.affiliation: Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: M Reza
authors.initials: MR
authors.lastname: Ghadiri
authors.affiliation: Center for Biopharmaceuticals and, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Christian A
authors.identifier: http://orcid.org/0000-0002-2953-8942
authors.initials: CA
authors.lastname: Olsen
mesh_terms: D001665:Binding Sites; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D056572:Histone Deacetylase Inhibitors; D047028:Macrocyclic Compounds; D010456:Peptides, Cyclic; D006655:Histone Deacetylases
keywords: depsipeptides; histone deacetylase inhibitors; macrocycles; peptides; total synthesis