Synthesis And Anti-Tumor Activity Of The Analogues Of High Unsaturated Fatty Acids And (9Z,12Z)-N-Cyclohexyl-N-(Cyclohexylcarbam Oyl) Octadeca-9,12-Dienamide

Objective: To synthesize two series of the ureide and the amide analogues of high unsaturated fatty acids.To observe the structure-activity relationship of hemolysis and anti-tumor activity of analogues.To screen compounds with antitumor activity and preliminary studies on anti-tumor activity in vivo.Methods: erucic acid,arachidonic acid,oleic acid,linoleic acid and linolenic acid were as raw materials.Scheme 1: these materials were coupled with DCC,DMAP as catalyst to synthesize the ureide compounds in 10 ?.Scheme 2: these materials were coupled with N,N-di(2-chloroethyl)amine hydro-chloride,pyridine as catalyst to synthesize the amide compounds.Isolation and purification were achieved by silical gel column chromatography,and these compounds structure were confirmed by 1H-NMR and 13C-NMR.The analogues were observed for the hemolysis according to the Chinese Pharmacopoeia hemolysis assay.Different tumor cell lines of Human hepatoma cell line(BEL-7404),Tongue cancer cell line(TCA-8113),Human lung cancer cell line(H-460)and Human Nasopharyngeal carcinoma cell line(CNE-2)were cultured in media with analogues of high unsaturated fatty acids,the cells growth was measured by MTT assay and calculating IC50.The compound with better inhibitory effects was screened out and obtained by acute toxicology experiment in vivo.It was established that the S180 Kunming mouse model of ascites tumor and solid tumors and it was observed that the inhibitory effects of the selected compounds on the life extension rate of S180 ascites tumor mice and the solid tumor of S180 mice.The anti-tumor effect of the selected compounds on the in vivo was determined.Results: 10 analogues of high unsaturated fatty acid were synthesized,which have no hemolytic effects on rabbit red blood cells in vitro.The inhibitory effects of MSR404,MSR405,MSR504 and MSR505 on the growth of BEL-7404,TCA-8113 and H-460 were significantly inhibited by anti-tumor activity in vitro.The toxic effects of MSR404 on mice were not observed in acute toxicity experiments.Under the condition of 480 mg/kg of the compound MSR404,the life-prolong in grate was 38.20%(P=0.049<0.05),and the inhibitory effect tumor growth of S180 was 71.2%(P=0.001<0.05).Conclusion: 10 compounds are synthesized successfully and 6 compounds among of them are novel.The synthesized 10 compounds have no hemolytic effects and compounds MSR404,MSR405,MSR504 and MSR505 have anti-tumor activities in vitro.The low toxicity of compound MSR404 has the anti-tumor effect in vivo,and it can be used as a new anti-cancer drug candidate for further study.