Design,Synthesis And Antitumor Activity Study Of Novel Histone Deacetylase Inhibitors And Amiodithioformate

The cancer mortality rate in china is 17%higher than that of the global average.Chemotherapeutic drugs still have poor target and toxic side effects.With the development of molecular biology,targeted anticancer drugs,natural anticancer drugs have been favored by researchers because of their low toxicity and side effects.Targeted drugs,such as histone deacetylase inhibitors(HDACi)are currently the focus of research,and SFA and SFE have become currently recognized as,among them,the best natural anti-cancer products.Once the SFA has enter the body,their isothiocyanate groups react with the thiol-containing amino acids to more stable aminodithioformates.Studies have shown that aminodithiocarbamate compounds have a wide range of biological activities,and considerable studies have found that amino-dithio compounds have better tumor prevention and anti-tumor activity.Firstly,the preseat work is focused on the design and synthesis of such histone deacetylase inhibitor compounds,including hydroxamic acids,benzamides and amides,and the structural modification of natural drugs SFA and SFE.The rationale behind this work is the expection that we could synthesize more stable and more effective anti-tumor drugs.Secondly,an in-vitro preliminary inhibition of cancer cell proliferation was performed on all synthesized compounds.The results showed that most compounds of aminodithiocarbamates have good inhibitory effects on cancer cells.R114 and R115 exhibited remarkable antiproliferative activity against SMMC-7721 with IC50 values of 5.31 ?M and 5.66?M,compared to SFE whose IC50 was 6.41?M.W115 and W120 exhibited remarkable antiproliferative activity against SMMC-7721 with IC50 values are 6.09?M and 6.12?M(IC50 of SFA is 7.87?M).Further investigation of colony formation and apoptosis of human hepatocellular carcinoma cell line SMMC-7721 showed that R114,R115 and W120 had a good inhibitory effect on cancer metastasis and proliferation.We also found that R114,R115 and W120 possessed potent induction for SMMC-7721 cancer cell cycle arrest at G2/M phase,and W115 arrest at G0/G1 phase.This study indicated clearly that R114 and W115 were the most promising drugs for the inhibition of SMMC-7721 cancer cells of all synthetic compounds.