title: Discovery, synthesis, and pharmacological evaluation of spiropiperidine hydroxamic acid based derivatives as structurally novel histone deacetylase (HDAC) inhibitors.
abstract: New spiro[chromane-2,4'-piperidine] and spiro[benzofuran-2,4'-piperidine] hydroxamic acid derivatives as HDAC inhibitors have been identified by combining privileged structures with a hydroxamic acid moiety as zinc binding group. The compounds were evaluated for their ability to inhibit nuclear extract HDACs and for their in vitro antiproliferative activity on different tumor cell lines. This work resulted in the discovery of spirocycle 30d that shows good oral bioavailability and tumor growth inhibition in an HCT-116 murine xenograft model.
authors.affiliation: Genextra Group, DAC SRL, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.forename: Florian
authors.initials: F
authors.lastname: Thaler
authors.forename: Agnese
authors.initials: A
authors.lastname: Abate
authors.forename: Chiara
authors.initials: C
authors.lastname: Bigogno
authors.forename: Roberto
authors.initials: R
authors.lastname: Boggio
authors.forename: Giacomo
authors.initials: G
authors.lastname: Carenzi
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cataudella
authors.forename: Roberto
authors.initials: R
authors.lastname: Dal Zuffo
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Fulco
authors.forename: Marco Giulio
authors.initials: MG
authors.lastname: Rozio
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Giulio
authors.initials: G
authors.lastname: Dondio
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids