Synthesis And Bioactibity Of L-a-Aminosuberic Acid-Based Histone Deacetylase Inhibitors

Histone acetylation is a major state of post-transcriptional modification associated with the DNA replication and gene activation. It is a reversible process regulated by two kinds of protease with mutually antagonistic function, which are histone deacetylase (HDAC) and histone acetyltransferase (HAT). The HDACs are related to cell cycle, transcriptional regulation and cell apoptosis. When HDACs are over-expression in cells and tissues, normal externalization of the cell cycle-regulation genes would be destroyed and and then resulting in turnorigenesis. Histone deacetylase inhibitors (HDACIs) cas.nodulate the acetylation status of histone N-terminal residues returning to normal by inhibiting the abnormal increases of HDACs and induce cell differentiation and apoptosis in tumour cells through regulation. The structures of HDACIs have the same functional areas:metal binding region, linkage region and the surface recognition region. HDACIs derivatives having a specificity against tumor cells would be screened through modification of the different functional areas. In this research, a series of novel HDACIs were designed and synthesized with the assistance of molecule docking approach, and the action mechanisms of the HDACIs and enzyme were preliminary explored.Hydroxamic acid, carboxylic acid and mono amide series derivatives based on L-a-aminosuberic acid scaffold were designed according to the structure and mechanism of SAHA which had been approved by United States for the treatment of T-cell Lymphoma as anti-cancer belongs to HDACIs class. The relationship between HDACIs inhibitory activity and structure was investigated by replacing the hydrophobic groups at the surface recognition region. Carboxylic acid series3a-3h, hydroxamic acid series5a-5c and mono amide series6d-6f were synthesized by means of solution-phase synthesis method. The designed compounds were measured by high performance liquid chromatography, Mass Spectrometry and Nuclear Magnetic Resonance.The inhibitory activity results of synthesized objective compounds3a-3h,5a-5c and6d-6f against HDAC1and HDACs showed that compounds5a-5c and6d-6f were at nanomolar level. At the same time, the anti-proliferation activities of these compounds against human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human hepatoma cells (HepG2and SMMC-7721) were detected, and hydroxamic acid series compounds5a-5c showed better inhibition activity. Compounds5a-5c and6d-6f were more inclined to inhibit hepG2cell than SMMC-7721cell. At100μM, the repression function of carboxylic acid series compounds against SMMC-7721cell were more significant increasing by25%than others.In order to understand the interaction characteristics of the inhibitors and enzyme, we chosen HDAC2for molecular docking. The mode action of all the compounds was similar to HDAC2. The connecting region with five methylenes occupied the channel of the enzyme activity pocket well, and hydrophobic interactions and hydrogen bonds were formed between inhibitors and the enzyme. Inhibitory action was enhanced for inhibitors and the enzyme because1-naphthyl group was introduced to the C-terminal of the cap, which could contribute to form more hydrogen bonds and make the binding free energy lower.In brief, we designed and synthesized a series of novel HDACIs derivatives based on the unnatural amino acid L-a-aminosuberic acid. After assessing the HDAC inhibitory activity and anti-proliferative activity against tumoi cells, all of the synthesized compounds were docking with HDAC2for conducting to further prove the interactions between inhibitors and HDACs. The results obtained would provide theoretical basis for designing novel HDACIs possessing subtype selective and high activity better.