Novel HDAC inhibitors with a phenylcinnamic scaffold: synthesis and evaluation of antitumor activity

Inappropriate epigenetic modifications of gene expression are associated with malignant phenotype and tumor progression. Regulation of gene expression is mediated by several mechanisms such as DNA methylation, ATP-dependent chromatin remodeling, and post-translational modifications of histones. Enzymes responsible for the reversible acetylation/deacetylation processes are histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Inhibitors of histone deacetylase (HDAC) enzymes have gained prominence as an emerging class of anticancer agents. We synthesized a series of hydroxamic acid-based HDAC inhibitors, characterized by a biphenyl-4-yl-acrylohydroxamic acid skeleton. The compounds were designed based on the hypothesis that the phenyl ring, extended from the hydroxamic acid via a double bond, could be suitable to occupy the narrow tube-like pocket of the HDAC active site. On the contrary, the cap structure appeared to accommodate in a large cavity, without a significant steric clash. Thus, a modification of the cap group appeared the most promising strategy to optimize drug-target interaction. Molecular docking was used to predict the optimal conformation of different molecules in the active site of a representative isoform from class I (HDAC2, sharing 85% sequence identity and 93% of sequence homology with HDAC1) and class II (HDAC6). From the results of docking studies three potential candidates with increased drug-target interactions were selected. All of them showed an activity towards HDAC1, 2 and 6 in the low µM range, estimated through a fluorimetric activity assay [2]. One of the compounds was further tested in vitro and in vivo in a colon carcinoma model and showed significant proapoptotic and antitumor activities.