title: Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors.
abstract: In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4'-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good in vitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors.
authors.affiliation: Genextra Group, Congenia Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy; Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy. Electronic address: florian.thaler@ieo.eu.
authors.forename: Florian
authors.initials: F
authors.lastname: Thaler
authors.affiliation: Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Loris
authors.initials: L
authors.lastname: Moretti
authors.affiliation: Genextra Group, Congenia Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy; Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Amici
authors.affiliation: Genextra Group, DAC Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy; Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Abate
authors.affiliation: NiKem Research Srl, Via Zambeletti 25, 20021 Baranzate, MI, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Colombo
authors.affiliation: Genextra Group, DAC Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy; Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Carenzi
authors.affiliation: Genextra Group, DAC Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy; Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Fulco
authors.affiliation: Genextra Group, Congenia Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Boggio
authors.affiliation: NiKem Research Srl, Via Zambeletti 25, 20021 Baranzate, MI, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Dondio
authors.affiliation: NiKem Research Srl, Via Zambeletti 25, 20021 Baranzate, MI, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Gagliardi
authors.affiliation: European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy; University of Milan, University of Milan, Via Celoria 26, 20133 Milan, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Genextra Group, DAC Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy; Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Sartori
authors.affiliation: Genextra Group, DAC Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy; Drug Discovery Program, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.affiliation: Genextra Group, DAC Srl, Genextra Group, Via Adamello 16, 20139 Milan, Italy. Electronic address: ciro.mercurio@ieo.eu.
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
mesh_terms: D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002867:Chromones; D056572:Histone Deacetylase Inhibitors; D013141:Spiro Compounds; D006655:Histone Deacetylases
keywords: Antiproliferation; Epigenetics; Histone deacetylases; Molecular modeling; Privileged structures