Design,Synthesis And Activity Evaluation Of Demethylepipodophyllotoxinyl O-Nitroaromates

Tumour is a major threat to global human health and chemotherapy plays an important role in the treatment of tumour.But in the process of chemotherapy,it is easy to produce serious side effects because of the low selectivity of chemotherapy drugs.Therefore,finding novel antitumour agents with low toxicity and high effect has currently become the focus of oncology.Podophyllotoxin(PDT),a kind of aryltetralin lignans extracted from plant podophyllotoxin,shows a pronounced biological activity mainly as antitumor and antiviral agents.However,they still have several limitations such as serious toxicity,side effects and poor water solubility.So researchers are trying to find other new derivatives of podophyllotoxin that could overcome such deficiencies.Etoposide(VP-16)and teniposide(VM-26),possessing antitumor activity,have been widely used as antitumour drugs for clinical chemotherapy.But,their low water solubility and serious side effects promote people to search for new derivatives of podophyllotoxin.Based on the research of podophyllotoxin derivatives,we found 4β-amines substituted demethylepipodophyllotoxin derivatives have superior antitumour activity and water solubility than others.In the meantime,on the basis of the differet environment between the tumor cells and normal cells such as low oxygen,low pH,high activity of reductase and electrical and steric structures of drug delivery systems,using ‘association principle’ in medicinal chemistry,we have designed and synthesized a series of o-Nitroaroyl-4β-amines demethylepipodophyllotoxin o-Nitroaromates.Twenty target compounds with electron-donating group,steric effect group electron-withdrawing group and comprehensive group were synthesised by several chemical reaction steps and structures were confirmed by 1H NMR,13 C NMR and ESI-MS.The cell proliferation inhibitory activity of the newly synthesized compounds by MTT assay shows that they all have less toxicity to normal cells than VP-16.Cell Apoptosis were determined by AnnexinV/PI assay,which turned out that 2b and 2d has better inducing apoptosis effect on Hela than VP-16.The cell cycle experiment found that 2b and 2d decreased dosing group G0/G1 phase but increased G2/M and S phase and blocked cell cycle in G2/M phase by PI staining.