The Anti-cancer Detection Of Bi-cyclic Histone Deacetylase Inhibitors

Histone deacetylase inhibitor, as a targeted inhibitor for histone deacetylases, possessed the ability of promoting acetylation, loosing chromatin, activing the expression of anti-tumour genes and inhibiting tumorigenesis. Of all kinds of inhibitors, cyclic-peptide inhibitors characterized by stabilization, relatively better efficacy and limited study. In addition, their anti-tumour mechanisms were still up in the air which needed more and more studies to explore deeply.All the synthetic cyclic-peptide inhibitors were firstly summarized and classified according to the metal-binding region of inhibitors and the special features existed in their frames. Molecular docking operated by Autodock Tools4.2with100runs was applied to screen preliminary for the inhibitors possessed comparably lower binding free energy. Just as the results indicated, seven inhibitors including5,8,9,58,59,60and61, showed better binding with HDAC2and HDAC4. Furthermore, bicyclic-peptide inhibitors (7,8,9), synthesized in our laboratory, were decided for next detection.Docking with150runs was used to know the surface recognition and hydrophobic interaction between bicyclic inhibitors1-5(5-9reffered above) and HDAC2, HDAC4, HDAH. Results showed a better selectivity of cyclic-peptide inhibitors to HDAC4either in aspect of binding free energy or interaction mode. During the next in vitro cytotoxicity-test (MTT) referring MCF-7, Hela, SMMC-7721, HL60, K562and U937, the best inhibitory effect of inhibitor4was found which was familiar with former enzyme inhibitory results, together with the outstanding difference of bicyclic-peptide inhibitor4to three leukemia cell lines which was choosed as the next research point.Nuclear stain, cell cycle detection and cell apoptosis induction tests were further verified the anti-leukemia function of inhibitor4. The obvious shrinking and splitting of nuclear, different levels of cell cycle arrest were all found in these tests, U937cells were arrested obviously at G2/M phase. Cell apoptosis of leukemia cell lines induced by inhibitor4were obsessed by flow cytometry, K562cell line was induced apoptosis to a larger extent than HL60and U937cell lines.Above all, bicyclic-peptide histone deacetylase inhibitors did possess a good anti-proliferation, apoptosis-induction and cell cycle arrest capabilities. Leukemia has been regarded as one of the hardest diseases all over the world, some thesis about histone deacetylase inhibitors applied into leukemic treatment were published before. Hence, this kind of inhibitors might be promising in leukemia therapeutic market with much more and deeper clinical studies done.