title: Non-natural macrocyclic inhibitors of histone deacetylases: design, synthesis, and activity.
abstract: Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the suberoyl-based macrocycles, which were expected to bear a maximum common substructure required to target the whole HDAC panel. A nanomolar HDAC inhibitory profile was observed for several compounds, which was comparable, if not superior, to that of 2. A promising cytotoxic activity was found for selected macrocycles against lung and colon cancer cell lines. Further elaboration of selected candidates led to compounds with an improved selectivity against HDAC6 over the other isozymes. Pair-fitting analysis was used to compare one of the best candidates with the natural tetrapeptide apicidin, in an effort to define a general pharmacophore that might be useful in the design of surrogates of peptidic macrocycles as potent and isoform-selective inhibitors.
authors.affiliation: Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Centre-ville, Montréal, QC, H3C 3J7 Canada.
authors.forename: Luciana
authors.initials: L
authors.lastname: Auzzas
authors.forename: Andreas
authors.initials: A
authors.lastname: Larsson
authors.forename: Riccardo
authors.initials: R
authors.lastname: Matera
authors.forename: Annamaria
authors.initials: A
authors.lastname: Baraldi
authors.forename: Benoît
authors.initials: B
authors.lastname: Deschênes-Simard
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Battistuzzi
authors.forename: Grazia
authors.initials: G
authors.lastname: Gallo
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciacci
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
mesh_terms: D045744:Cell Line, Tumor; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular
chemical_list: D056572:Histone Deacetylase Inhibitors; D047028:Macrocyclic Compounds