Polyaminobenzamides and related analogues as isoform-selective histone deacetylase inhibitors

The remodeling of chromatin between relatively open and closed forms has a key role in epigenetic regulation of gene expression; including numerous genes that mediate tumorigenesis. Such remodeling results from modifying the structure of nucleosome by a range of modifications of the amino-terminal 'tails' of histones. Among them hsitone acetylation and deacetylation by opposing activities of histone aceyltransferase and hsitone deacetylase tightly regulate gene expression through chromatin modification. Aberrant histone deacetylase (HDAC) activity promotes chromatin condensation and inhibits expression of tumor suppressor factors; by contrast, HDAC inhibition caused by HDAC inhibitors such as trichostatin (TSA), MS-275 and SAHA results in tumor growth inhibition in wide range of transformed cells. Traditional HDAC inhibitors lack isoform specificity, and can produce toxicity to noncancerous cells. Hence polyamine derivatives, polyaminohydroxamic acid (PAHA) and polyaminobenzamide (PABA) analogues can be used as HDAC inhibitors to reduce toxicity, increase the affinity for chromatin and to have potential for uptake by the polyamine transporter. Specific interaction of the polyamine moiety with the HDAC rim region could also improve isoform specificity.;First generation of polyamino HDAC inhibitors, PAHAs were synthesized earlier in our laboratory and they were potent HDAC inhibitors, but poor substrates for the transporter. Hence, we designed second generation of polyamino HDAC inhibitors, additional PABA derivatives and isosteric homologues to improve isoform specificity and polyamine transportability. Most of the compounds with various structural features seem to inhibit HDACs in enzyme assay and some of them have shown considerable selectivity for HDAC 1 against HDAC 3, 6 and 8 and in cultured tumor cells. Among this small library of compounds, one compound showed promising cytotoxiciy effect in human breast tumor cells compared to normal breast epithelial cells.;In this dissertation, we report the synthesis of PABAs and isosteric homologues and their activity against HDAC isoforms and their biological evaluation in tumor cells.