1. Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] based histone deacetylase inhibitors.
- Author
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Thaler F, Varasi M, Abate A, Carenzi G, Colombo A, Bigogno C, Boggio R, Zuffo RD, Rapetti D, Resconi A, Regalia N, Vultaggio S, Dondio G, Gagliardi S, Minucci S, and Mercurio C
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Benzoxazines chemical synthesis, Benzoxazines chemistry, 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, Humans, K562 Cells, Mice, Microsomes, Liver chemistry, Microsomes, Liver metabolism, Molecular Structure, Neoplasms, Experimental pathology, Spiro Compounds chemical synthesis, Spiro Compounds chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Benzoxazines pharmacology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Neoplasms, Experimental drug therapy, Spiro Compounds pharmacology
- 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., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
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