title: Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] based histone deacetylase inhibitors.
abstract: Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues.
authors: Genextra Group, Congenia s.r.l., Via Adamello 16, 20139 Milan, Italy. florian.thaler@ieo.eu
authors: Florian
authors: F
authors: Thaler
authors: Mario
authors: M
authors: Varasi
authors: Agnese
authors: A
authors: Abate
authors: Giacomo
authors: G
authors: Carenzi
authors: Andrea
authors: A
authors: Colombo
authors: Chiara
authors: C
authors: Bigogno
authors: Roberto
authors: R
authors: Boggio
authors: Roberto Dal
authors: RD
authors: Zuffo
authors: Daniela
authors: D
authors: Rapetti
authors: Anna
authors: A
authors: Resconi
authors: Nickolas
authors: N
authors: Regalia
authors: Stefania
authors: S
authors: Vultaggio
authors: Giulio
authors: G
authors: Dondio
authors: Stefania
authors: S
authors: Gagliardi
authors: Saverio
authors: S
authors: Minucci
authors: Ciro
authors: C
authors: Mercurio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048588:Benzoxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D048588:Benzoxazines; D056572:Histone Deacetylase Inhibitors; D013141:Spiro Compounds; D006655:Histone Deacetylases