Syntheses and biological evaluation of polyamine derivatives as histone deacetylase inhibitors

The reversible acetylation of histones, mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), plays an important role in chromatin architecture and hence in regulation of gene expression. Acetylation of cationic lysine tails in nucleosome-associated histones neutralizes charge and promotes relaxation of chromatin, 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 and thus contributes to the development of cancer. Histone hyperacetylation caused by HDAC inhibitors such as trichostatin (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. However these compounds are not selective against various isoforms of HDAC and are toxic to the normal cells. Hence we designed polyamine derivatives as histone deacetylase inhibitors because of following reasons: (a) Uptake of the molecule by polyamine transport system. (b) Nuclear localization and enhanced affinity for chromatin. (c) Specific interaction with amino acids outside binding area would impart isoform specificity.; Analogues of all the three naturally occurring polyamines were synthesized. The polyamine based derivatives had the structural features required by the traditionally active HDAC inhibitor. These were hydroxamic acid containing derivative and benzamide containing derivative. The benzamide derivatives were synthesized to increase the transport of the compounds by polyamine transport system, since hydroxamic acid containing derivatives were not well transported. All the compounds with respect to various structural features seem to inhibit HDAC in enzyme assays and in tumor cell lines. These compounds form a new class of HDAC inhibitors which can find wide applications in pathophysiology involving excess HDAC function.; In this dissertation the details of synthesis of the derivatives and their preliminary biological evaluations as HDAC inhibitors are reported.