Synthesis of novel hydroxamate and non-hydroxamate histone deacetylase inhibitors

Histone deacetylases (HDACs) alter the acetylation status of chromatin and thereby effect gene expression. The inappropriate recruitment of HDACs may be one mechanism by which oncogenes can alter gene expression in favor of excessive cell proliferation, making inhibition of HDACs a potential target for the development of small-molecule anticancer agents. As a consequence there are several HDAC inhibitors currently undergoing clinical trials for the treatment of solid and non-solid tumors. This review examines recent synthetic methods used to prepare the diverse family of HDAC inhibitors, and includes syntheses of several of the current clinical candidates. The review is divided into the structural classes of known HDAC inhibitors, including non-peptidic hydroxamic acids, non-hydroxamate analogs and cyclic peptides.