SAR studies on HDAC inhibitors featured by phenyl-4-yl-acrylohydroxamic acids scaffolds

Epigenetic mechanisms are crucial for normal development and maintenance of tissue-specific gene expression patterns in mammals. Aberrant epigenetic programming can lead to altered gene function and malignant cellular transformation. The main epigenetic modifications in mammals are DNA methylation and posttranslational histone modifications (acetylation, methylation, phosphorylation, etc.). The acetylation status of histones and non-histone proteins is determined by histone deacetylases (HDACs) and histone acetyl-transferases (HATs). Altered expression and mutations of genes that encode HDACs have been linked to tumor development since they both induce the aberrant transcription of key genes regulating important cellular functions (i.e. cell proliferation, cell-cycle regulation and apoptosis). Thus, HDACs are among the most promising therapeutic targets for cancer treatment, and they have inspired researchers to study and develop HDAC inhibitors.1 Inhibition of HDACs causes histone hyperacetylation with transcriptional activation of genes associated with cell cycle arrest or apoptosis in tumor cells. Typically, HDAC inhibitors contain three regions: a 'cap' region or 'surface recognition domain', a 'zinc-binding group', chelating the zinc ion in the active site, and a 'linker' region, connecting the two moieties.2 We have developed a series of hydroxamic acid-based compounds, characterized by a cinnamic spacer capped with a substituted phenyl group. Here we report the SAR studies on these compounds and our efforts to optimize the drug-target interaction by modification of the cap group and the ZBG-functionality. Whereas most of the candidates with alternative Zn-binding groups were less effective than the parent hydroxamic acid, selected compounds modified in the cap region showed an activity towards HDAC2 in the low \ub5M range, assessed through a fluorimetric assay. One of the compounds was further tested in vitro and in vivo in a colon carcinoma model and showed significant proapoptotic and antitumor activity