Synthesis And Evaluation Of Anticancer Activity Of A Series Of 4?-carbamoyl 4'-O-demethylepipodophyllotoxins

This thesis is divided into two parts:the first part is synthesis and evaluation of anticancer activity of a series of 4?-carbamoyl 4'-O-demethylepipodophyllotoxins,which is based on the excellent anticancer activity of podophyllotoxin;and the second part is about synthesis process of 2-Deoxy-D-Glucose,as a potential antiviral compound.1.Podophyllotoxin(PPT)extracted from the roots and rhizomes of Podhyllum species such as Podophyllum hexandrum and Podophyllum peltatum,has cathartic,antirheumatic,antiviral properties,and antimitotic activity.By using PPT as a lead compound,structural modification of it leads to the emergence of less toxic,useful anti-cancer drugs namely,etoposide and teniposide,which are thus successfully utilized in treatment of a variety of cancers,including lymphoma,testicular carcinoma,small-cell lung cancer,and Kaposi's sarcoma.However,their therapeutic uses are often hindered by problems such as acquired drug-resistance and poor water-solubility.To search for the anticancer agents with high activity and low toxicity,we synthesized a series of 4?-carbamoyl 4'-O-demethylepipodophyllotoxin and evaluated their cytotoxicities against a panel of four human cancer cell lines.Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide.The IC50 value of 4?-4'-demethylepipodophyllotoxin 1-(4-nitrophenyl)piperazinyl carbamate,the most potent compound of those synthesized in the current study,is 0.074,1.67,<0.01 and 0.17?M for HeLa,A549,HCT-8 and HL-60,respectively.This compound induced cell cycle arrest in the G2/M phase in HeLa cells,which was accompanied by apoptosis,and activated the expression of Bax,p53 and caspase-3 in HeLa cells,leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form.These results suggest that these compounds have potential for further development as anticancer agents.2.2-Deoxy-D-Glucose(2-DG)is a natural compound which has antiviral properties and antimitotic activity.It is usually used to prevent virus and pathogen infection including SV?HIV?SARS and so on.Therefore,2-DG has a broad application prospect and huge market demand.According to the reports,synthesis of 2-DG still has many shortcomings,such as harsh reaction conditions,low total yield and long production cycle.In order to research new synthetic methods for industrial production of 2-DG,the paper is based on cheap glucose,designing two synthetic routes to get 2-DG efficiently by common chemical reactions including esterification,substitution,hydrolysis.The total yield reached 46%and 58%,which will lay a good foundation for mass production of 2-DG in the future.