Design and synthesis of novel pyrimidine hydroxamic acid inhibitors of histone deacetylases

Inhibition of histone deacetylase activity represents a promising new modality in the treatment of a number of cancers. A novel HDAC series demonstrating inhibitory activity in cell proliferation assays is described. Optimisation based on the introduction of basic amine linkers to effect good drug d...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (22), p.6657-6660
Hauptverfasser:	Donald, Alastair D.G., Clark, Vanessa L., Patel, Sanjay, Day, Francesca A., Rowlands, Martin G., Wibata, Judata, Stimson, Lindsay, Hardcastle, Anthea, Eccles, Sue A., McNamara, Deborah, Needham, Lindsey A., Raynaud, Florence I., Aherne, Wynne, Moffat, David F.
Format:	Artikel
Sprache:	eng
Schlagworte:	Acetylation Antineoplastic agents Biological and medical sciences Cancer Cell Line, Tumor Drug Design General aspects HDAC Histone Deacetylase Inhibitors - chemical synthesis Histone Deacetylase Inhibitors - chemistry Histone Deacetylase Inhibitors - pharmacology Humans Hydroxamic Acids - chemical synthesis Hydroxamic Acids - chemistry Hydroxamic Acids - pharmacology Medical sciences Optimisation Pharmacology. Drug treatments Pyrimidines - chemistry Transplantation, Heterologous
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Zusammenfassung:	Inhibition of histone deacetylase activity represents a promising new modality in the treatment of a number of cancers. A novel HDAC series demonstrating inhibitory activity in cell proliferation assays is described. Optimisation based on the introduction of basic amine linkers to effect good drug distribution to tumour led to the identification of a compound with oral activity in a human colon cancer xenograft study associated with increased histone H3 acetylation in tumour tissue.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.09.016