Synthesis, characterization, and evaluation of Cd[L-proline] 2 , a novel histone deacetylase inhibitor that induces epigenetic modification of histone deacetylase isoforms in A549 cells

SummaryHistone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression through their effects on the compact chromatin structure. In clinical studies, several classes of histone deacetylase inhibitors (HDACi) have demonstrated potent anticancer activities with metal complexes. Hence, we synthesized cadmium –proline complexes using both the D- and L-isomers of proline and evaluated their biological activities by observing the efficiency of their inhibition of HDAC activity, ability to reduce the expression of HDAC isoforms in A549 cells and effect on apoptosis. The synthesized compounds were characte rized by UV, IR, NMR spectroscopy and elemental analysis. In-vitro cell toxicity was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and the 50% inhibitory concentration (IC50; 2  μM) was obtained at 12 h. The morphological study at nuclear levels was performed by acridine orange/ethidium bromide (AO/EB) and Hoechst staining, and the results showed an association with cell cycle arrest at the G2/M phase. Both cadmium–proline complexes intensely inhibited HDAC activity a t 2 μM concentration. Interestingly, Cd[L-proline]2 was found to be a potent inhibitor for all HDAC isoforms, whereas Cd[D-proline]2 inhibited only HDAC1 and 2. HDACi are novel chemotherapeutic drugs that induce hyperacetylation of histones H3 and H4, counteracting the aberrant repression of genes, such as insulin-like growth fa...
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research