Synthesis Of Deguelin-Amino Acid Derivatives And Research On Its Anti-Lung Tumor Effects

Objective:Lung cancer is one of the world’s cancer which has highest morbidity and mortality.Developing anti-cancer drugs with low toxic and sustainable development is a very urgent task in lung cancer treatment.A large number of studies have shown deguelin’s significant effect in lung cancer prevention and treatment,no matter treat alone or adjuvant.Its therapeutic effect and mechanism of lung cancer has been confirmed.Although most of the vitro and vivo studies have shown that anti-tumor effect of deguelin is good,and there is no visible side effects,it is a natural antitumor compound with great potential.There are also paper reported that when high concentration or long time of deguelin treatment,the experimental mice will appear the symptoms similar to Parkinson’s disease.The neurotoxicity of deguelin make it no possible to use for large dose or long time,hinder its development into anti-tumor drugs.Modificating its structure to improve its antitumor activity and bioavailability or decrease its toxicity is one of the important direction in cancer research of deguelin.The main contents of this paper are as follows:(1)Synthesis the active site with reference to the paper,obtain 8 kinds of ring-truncated deguelin and amino acid deravatives 3A-3H,the structures were characterized by 1HNMR、13CNMR and LC-MS.(2)The antitumor activity in H1299 lung cancer cells was testified by CCK8,and obtain 3C、3D which show the best anticancer activity.Evaluate its activity of induce tumor apoptosis with AO-EB staining.(3)The zebrafish experiment: Evaluate its inhibition of zebratish embryo development in different concentration during the same period or same concentration during the different period.AO staining to observe its effect in promoting apoptosis;(4)Toxicity experiment: Test the drug toxicity to normal cell and nerve cell using CCK8 assay in normal HBE lung cell and SH-SY5 Y cell.Observe its effect on 24 hpf、48 hpf、72 hpf zebrafish when administration in shield or 24 hpf to evaluatie its general toxicity fo zebrafish embryos.Administration in 24 hpf,make paraffin section of the brain and HE staining of 7 dpf embryos to test its neurotoxicity.The conclusion is as follows:3C、3D inhibite H1299 lung cancer cell proliferation and induce its apoptosis of it without toxicity effect on normal HBE lung cells and SH-SY5 Y nerve cell.In vivo,3C、3D inbibite the development of zebrafish and induce apoptosis.The anti caner effect of 3C and 3D is less active than deguelin.But then overcome the side effect of deguelin on nerve and provide reference to deguelin structure modification.