Synthesis And Preliminary Activity Study Of Novel Hydroxamate Acids Derivatives As Histone Deacetylases Inhibitors

Cancer is one of the three severe diseases harmful to human health. At the21th WorldCancer Congress held in Shenzhen, China,2010. The international union of anti-cancerreleased the data which showed that there were12.7million people in the world that hadcancer in2008,the death number were as high as7.6million, which was equivalent to lessthan five seconds there was a cancer patient dead. There will be26million new cancercases every year and the death number of cancer will reach to17million by2030. In China,cancer incidence is rising rapidly. There will be2.6million people having cancer every year,1.8million among them will be died. As is known to all, the traditional drug treatment havemany side effects such as significant toxicity, low selectivity, multidrug resistance and soon. So in recent years, the small molecule targeted therapy drugs become one of thehotspots of anticancer drugs. Currently, more and more research showed that the histonedeacetylases(HDACs) had a very close relationship with the development of tumor. Giventhe pleiotropic functions of HDACs in tumorigenesis and development, the diverseantitumor mechanisms of HDACs inhibitors are slowly unfolding: inducing tumor cellapoptosis and autophagy, causing tumor cell cycle arrest, anti-angiogenesis, reducing DNAdamage repair, enhancing chemotherapy and radiotherapy, reducing tumor cell invation and motility, etc. Among them, the most studied and the best compounds are hydroxamic acidderivatives as HDACs inhibitors. The experiment synthesized16new hydroxamic acids, inorder to investigate the inhibitory effect on lung cancer cells. In this paper, we will discussas the following four aspects:Firstly, advance research on the synthetic method and the pharmacological activity ofhydroxamic acids are summarized.Secondly, the synthesis process of the important intermediates named Ethyl3-aminobenzoate. The effects of factors, such as catalyst type, amount of catalyst, ethanoldosage, reaction time on the reaction yield were investigated. The better synthesis processwas selected-(n)acid:(n)alcohol:(n)catalyst=1:26:2.8reflux reaction8h, under theseconditions the yield reached94%. The product was characterized by IR.Thirdly, synthesis of the target compounds. Synthesis of eighteen compounds:3-Aminobenzoyl hydroxamic acid(MHA),3-[N-[(4-chloro-benzylidene)methylidene]amino]hydroxamic acid(4a),3-[N-[(4-Bromo-benzylidene)methylidene]amino]hydroxamic acid(4b),3-[N-[(4-Diethylamino-benzylidene)methylidene]amino]hydroxamic acid(4c),3-[N-[(4-Nitro-benzylidene)methylidene]amino]hydroxamic acid(4d),3-[N-[(4-hydroxy-benzy-lidene)methylidene]amino]hydroxamic acid(4e),3-[N-[(5-chloro-2-hydroxy-benzylidene)methylidene]amino]hydroxamic acid(4f),3-[N-[(2-hydroxy-naphthalen-1-ylmethylene)met-hylidene]amino]hydroxamic acid(4g),3-[N-[(3,5-Dichloro-benzylidene)methylidene]amino]hydroxamic acid(4h) and4-Aminobenzoyl hydroxamic acid(PHA),4-[N-[(4-chloro-benzylidene)methylidene]amino]hydroxamic acid(5a),4-[N-[(4-Bromo-benzylidene)meth-ylidene]amino]hydroxamic acid(5b),4-[N-[(4-Diethylamino-benzylidene)methylidene]amino] hydroxamic acid(5c),4-[N-[(4-Nitro-benzylidene) methylidene]amino]hydroxamicacid(5d),4-[N-[(4-hydroxy-benzylidene)methylidene]amino]hydroxamic acid(5e),4-[N-[(5-chloro-2-hydroxy-benzylidene)methylidene]amino]hydroxamic acid(5f),4-[N-[(2-hydroxy-naphthalen-1-ylmethylene)methylidene]amino]hydroxamic acid(5g),4-[N-[(3,5-Dichloro-benzylidene)methylidene]amino]hydroxamic acid(5h). Using m-ABHA and p-ABHA asmaterial. Melting point test,1H-NMR and MS were used to determine the structure of the18kinds of target compounds. Through the CA and Beilstein database retrieval, I finally made sure that16compounds of them hadn’t been reported both home and abroad.Fourthly, with human lung cancer cell line A549as the research object, which weremeasured by MTT assay. The7compounds:4a,4c,4g,5a,5c,5g and3-amino-phenylhydroxamic acid, were choosed as representative drugs to inhibit the lung cancer cell lineA549at five concentration12.5μmol/L,25μmol/L,50μmol/L,100μmol/L and200μmol/L. Observing the inhibition and calculating the50%inhibitory concentration(IC50)after48hours later. And the IC50values were82.102μmol/L、61.570μmol/L、64.789μmol/L、39.938μmol/L、53.606μmol/L、61.424μmol/L、52.886μmol/L, respectively. Theresults showed that all the compounds had an obvious inhibition on the lung cancer cell lineA549proliferation and in a dose-dependent manner.