Design,Synthesis And Biological Evalucation Of Novel Histone Deacetylase Inhibitors As Potent Antitumor Agents

Cancer is a widespread disease with high mortality.Traditional antitumor drugs usually result in seriously side effect because of lacking targeted therapies.In the last decade,histone deacetylases(HDACs)have become promising targets for cancer therapy.To date,five HD AC inhibitors have been approved.The approved HD AC inhibitors can be divided into two categories:hydroxamic acids represented by SAHA and benzamides represented by chidamide.SAHA possesses potent anticancer activity but no selectivite inhibitory against HDAC isoforms.Chidamide possesses selectivite inhibitory against HDAC isoforms but the antitumor activity of chidamide is still not high enough.The common pharmacophore of HDAC inhibitors consists of three portions:(1)ZBG,a zinc binding group chelating Zinc at the bottom of HDACs active site;(2)a CAP group,interacting with the surface of HDACs;(3)a linker connecting the ZBG and the CAP group.In order to obtain more valuable candidates for cancer therapy,we designed,synthesized and evaluated a series of novel HDAC inhibitors.The main contents of the thesis are as follows:Firstly,we designed,synthesized and evaluated a series of HD AC inhibitors with amine or ether as CAP group.Amines and ethers are common pharmacophores of drugs.In this thesis,the CAP group of chidamide was replaced by amine or ether,and the 2-aminobenzamide structure of chidamide was replaced by hydroxamic acid.A total of 20 target compounds were synthesized.Compounds 12a,15a and 16a displayed significantly more potent antiproliferative activity than chidamide.Furthermore,the toxicity of compound 12a was very low,and the maximum tolerated dose of mouse was greater than 2000 mg/kg.Although compound 12a is rapidly metabolized in mice,compound 12a is a potent selective inhibitor of HDAC2 and is very important for the development of novel selective HDAC inhibitors.Further structure optimization of 12a is under way in our lab to obtain more potent HD AC inhibitors for cancer therapySecondly,we designed,synthesized and evaluated a series of HDAC inhibitors with dithiocarbamate as CAP group.Dithiocarbamates are a common class of organic molecules,exhibiting a wide range of biological activities,including antibacterial and antitumor.Considering the variety biological activities of dithiocarbamates,we were interested in introducing dithiocarbamate as the cap group of HDAC inhibitors to improve their potencies as HDAC inhibitors and antitumor agents.We synthesized 34 target compounds.Compounds M101,M122 and M133 displayed significantly more potent antiproliferative activity than chidamide.We also designed and synthesized 9 derivatives of M101 and found that the bromo-substituted derivatives N106 and N109 displayed significantly more potent HD AC 1 and HDAC2 inhibitory activity and antiproliferative activity than M101.We also designed and synthesized 35 HD AC inhibitors with dithiocarbamate as CAP group and alkyl as linker group.Compound Q111 displayed significantly more potent antiproliferative activity than chidamide against A549 cancer cells.Furthermore,the toxicity of M101,M122 and M133 were very low,and the maximum tolerated dose of mouse was greater than 2000 mg/kg.But compounds M101,M122 and M133 are rapidly metabolized in mice.Further structure optimization to increase the in-vivo half-life of the compounds are under way in our lab to obtain more valuable HD AC inhibitors for cancer therapyThirdly,we designed and synthesized DNA/HD AC dual targeting compounds.the nitrogen mustards represent a major class of genotoxic anticancer drugs for the treatment of various cancers.The mechanism of action of nitrogen mustard is based on attacking cellular DNA and causing DNA damage.Recent evidence demonstrates that HD AC inhibitor is able to down regulate the DNA damage repair machinery.Thus,we combined pharmacophores of nitrogen mustard drugs and HD AC inhibitors to obtain dual-targeting potent antitumor agents.We designed and synthesized a chlorambucil derivative named vorambucil with a hydroxamic acid tail as a DNA/HDAC dual-targeting inhibitor.We also designed and synthesized a compound named chlordinaline containing nitrogen mustard and 2-aminobenzamide moieties as a DNA/HDAC dual-targeting inhibitor.Both two compounds obtained HDACs inhibitory activity and displayed more potent DNA damage activity and antiproliferative activity than chlorambucil.Notably,chlordinaline exhibited excellent selective inhibition against HDAC3.The excellent selectivity of chlordinaline against HDAC3 was well rationalized by molecular docking results.These two DNA/HDAC dual-targeting inhibitors could be promising candidates for cancer therapy and also could be lead compounds for further optimization to obtain more potent DNA/HDAC dual-targeting inhibitors.In conclusion,in the guidance of organic chemistry,biochemistry and computational chemistry,a total of 137 target compounds were designed and synthesized in this project.Structures of target compounds were confirmed with HRMS,1H-NMR and 13C-NMR.Most compounds synthesized in our work displayed potent HDACs inhibitory activity and antiproliferative activity.Many of them were able to inhibit colony formation,induce apoptosis and arrest cell cycle of cancer cells.This thesis provided a new insight of the discovery of novel HD AC inhibitors as potent antitumor agents.