Discovery of histone deacetylase inhibitors with new zinc binding groups

The reversible acetylation of histones, mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), plays a critical role in chromatin architecture and hence in regulation of gene expression. Acetylation of lysine tails in histones neutralizes charge and promotes relaxation of chromatin, thus leading to transcriptional activation. Conversely, deacetylation of these lysine residues promotes formation of condensed chromatin, and transcription is repressed. In some tumor cell types, excessive hypocetylation of histones results in the underexpression of growth regulatory factors such as the cyclin dependent kinase inhibitor p21Waf1/CIP1 and thus contributes to the development of cancer. Histone hyperacetylation caused by HDAC inhibitors such as TSA, MS-275 and SAHA can cause growth arrest in a wide range of transformed cells and can inhibit the growth of human tumor xenografts. Although these inhibitors are effective both in vitro and in vivo, they suffer from lack of specificity among the various forms of HDAC, including deacetylases that target nonhistone proteins. Further, they also produce side effects through activity in noncancerous cells. Current structure activity studies of designing new HDAC inhibitors have largely focused on modifications to the aromatic ring moiety and the aliphatic linker region present in these molecules while studies on zinc binding groups are less emphasized, promoting us to design and synthesize a series of histone deacetylase inhibitors incorporated with new zinc binding groups. In this dissertation, two new zinc binding groups have been explored and applied into molecules to show the HDAC inhibitory activity. Most compounds show the preference to inhibit class I (HDAC1/2/3) and class Ilb (HDAC6/10) histone deacetylases. Furthermore, compound 54 from 2-(oxazol-2-yl)phenol class shows an impressive antiproliferative activity against various cancer cell lines and it can restore the expression of cyclin dependent kinase inhibitor p21Waf1/CIP1 which is an inhibitor of cell cycle progression. Since compound 54 shows better activity in cellular assay than enzymatic assay, which indicates that this compound may be a HDAC1/2 complex inhibitor. Molecular studies have been conducted to further study the interaction between compound 54 and enzyme active site and a similar zinc-binding mode with benzamide class HDAC inhibitors has been found, which may initiate a new class of HDAC inhibitors.