Chemistry and Biology of Chromatin Remodeling Agents: State of Art and Future Perspectives of HDAC Inhibitors

Abstract

Chromatin remodeling is a fundamental phenomenon in the life of eukaryotic cells, bearing implications to numerous physiological and pathological phenomena. This review outlines the chemistry of natural and synthetic agents endowed with the ability to interfere with such biological function, with a particular emphasis on histone deacetylase (HDAC) inhibitors. Other aspects covered in this article comprise structure activity relationships (SAR) and modes of action at molecular level, including the description of crystal structures of enzyme-inhibitor complexes.

Simple inhibitors of histone deacetylase activity that combine features of short-chain fatty acid and hydroxamic acid inhibitors

“…Inhibition of HDAC activity therefore has the effect of promoting the transcription of silenced genes. Application of HDAC inhibitors in cancer cell lines and mouse model systems leads to interruption of the cell cycle, differentiation, and apoptosis [3][4][5][6]. Clinical studies have shown tumor repression and improvement of patient symptoms without significant side effects.…”

“…Investigations of other short chain acids, such as 4-phenylbutyric acid and valproic acid (Figure 1), have shown them to be effective against similar cancer cell lines [16,17]. Although 4-phenylbutyric acid's in vitro efficacy is low, it was the first HDAC inhibitor to be evaluated in clinical trials [3]. Valproic acid, a drug currently used to treat epilepsy and bipolar disorder, has a significantly longer half-life than sodium butyrate and has an established clinical record [16].…”

Embryonic Life of Hdac Inhibitors: – In Diabetic Nephropathy

“…Hyperacetylation [2,24,25] results in an increase in the space between the nucleosome and the DNA that is wrapped around it. The opening of chromatin structure subsequently provides the access for gene transcription.…”

“…[2] Inhibitors of HDACs regulate gene transcription through hyperacetylation of nucleosomal histone and non-histone proteins. [24,25] HDACIs also have effects on non-histone proteins which include proteins involved in the regulation of gene expression, pathways of extrinsic and intrinsic apoptosis, cell-cycle progression, redox pathways, mitotic division, DNA repair, cell migration and angiogenesis. [2,[33][34][35][36][37][38][39] In general, amplified levels of histone acetylation lead to de-condensation of chromatin allowing DNA accessible to transcription factors, and are thus related with increased transcriptional activity, whereas decreased acetylation levels are associated with transcriptional repression.…”

HIV Type-1 Latency: Targeted Induction of Proviral Reservoirs

“…VA has been used at concentrations approaching 1 mM in vitro [47], doses that are impossible to achieve clinically. HDAC inhibitors with activity in the nanomolar range have been reported [48] and these might be useful in obtaining maximal benefit from a purging strategy. …”