Discovery, Synthesis, and Pharmacological Evaluation of Spiropiperidine Hydroxamic Acid Based Derivatives as Structurally Novel Histone Deacetylase (HDAC) Inhibitors

• Published in: Journal of medicinal chemistry 2011-04, Vol.54 (8), p.3051-3064
• Main Authors: Varasi, Mario, Thaler, Florian, Abate, Agnese, Bigogno, Chiara, Boggio, Roberto, Carenzi, Giacomo, Cataudella, Tiziana, Dal Zuffo, Roberto, Fulco, Maria Carmela, Rozio, Marco Giulio, Mai, Antonello, Dondio, Giulio, Minucci, Saverio, Mercurio, Ciro
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological Availability; Cell Line, Tumor; Drug Evaluation, Preclinical; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Magnetic Resonance Spectroscopy; Mice; Molecular Structure; Spectrometry, Mass, Electrospray Ionization
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200146u

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.