Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] based histone deacetylase inhibitors

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. Here...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2013-06, Vol.64, p.273-284
Main Authors: Thaler, Florian, Varasi, Mario, Abate, Agnese, Carenzi, Giacomo, Colombo, Andrea, Bigogno, Chiara, Boggio, Roberto, Zuffo, Roberto Dal, Rapetti, Daniela, Resconi, Anna, Regalia, Nickolas, Vultaggio, Stefania, Dondio, Giulio, Gagliardi, Stefania, Minucci, Saverio, Mercurio, Ciro
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antiproliferation
Benzoxazines - chemical synthesis
Benzoxazines - chemistry
Benzoxazines - pharmacology
Cell Cycle - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HCT116 Cells
HeLa Cells
Histone Deacetylase Inhibitors - chemical synthesis
Histone Deacetylase Inhibitors - chemistry
Histone Deacetylase Inhibitors - pharmacology
Histone deacetylases
Histone Deacetylases - metabolism
Humans
Hydroxamates
In vivo antitumor activity
K562 Cells
Mice
Microsomes, Liver - chemistry
Microsomes, Liver - metabolism
Molecular Structure
Neoplasms, Experimental - drug therapy
Neoplasms, Experimental - pathology
Pharmacokinetics
Privileged scaffolds
Spiro Compounds - chemical synthesis
Spiro Compounds - chemistry
Spiro Compounds - pharmacology
Structure-Activity Relationship
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Summary: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. [Display omitted] •Spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] hydroxamates were designed and prepared.•Selected compounds showed good microsomal stability and reduced hERG affinity.•Two examples showed low clearance and good oral bioavailability in vivo.•The good PK properties translated in significant antitumor activity in vivo.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2013.03.061