Study On Synthesis And Anti-Metastatic Effects Of Amide Derivatives Of E-Salignone

Objective The previous studies of Professor Duan Hongquan’s group found that the natural product(E)-3β-Dimethylamino-pregn-17-en-16-one(E-Salignone)has a good anti-metastasis activity that the 50%inhibition concentration is 0.87 μM.In this paper,on the basis of comprehension of previous studies,E-Salignone was selected as a lead compound,three classes of amide derivatives were designed and synthesized through organic chemistry methods,the anti-metastatic activity have been determined and the preliminary structure-activity relationship was studied.Not only the experimental evidence was provided to further structuring optimization,but also a great quantity of instrumental compounds were supplied to study the mechanism of compounds of this class.Methods The amide derivatives have been prepared by Wittig reaction,Mitsunobu reaction,Gabriel synthesis,Riley reaction and amino protection reaction from the androsterone and epiandrosterone as starting materials.The chemical structures of all target compounds have been characterized by the organic spectroscopy and the anti-metastatic activity have been determined by migration assay of mastocarcinoma cells,the structure-activity relationship was analysised comprehensively.Results 1.There were sixty eight compounds synthesized by organic chemistry methods,including eight intermediates and sixty derivatives.All the compounds were identified by organic spectrum methods.All the derivatives were the new compounds which hadn’t been reported before.2.To make sure the screening non-cytotoxic doses of anti-metastatic activity,MTT test was taken on 32 amide derivatives.It turned out that overwhelming majority of compounds did not have cytotoxicity,Compound 18h,19c and 19e have higher cytotoxicity,their cell growth inhibition can reach 86.10%,79.30%and 81.50%under the concentration of 25μM respectively.Anti-metastasis experiment on 37 amide derivatives showed that Compound 18f,6a and 23 have significant anti-metastasis activity,in which inhibition ratio of 18f is 60.50%when the concentration is 2.5μM.Conclusion In this paper,three classes of 60 E-Salignone amide derivatives were synthesized through multistreaction from the androsterone and epiandrosterone as starting materials,Which were all the new compounds hadn’t been reported before.Anti-metastasis experiment on parts of amide derivatives showed that 16-carbonyl derivatives usually had stronger activity,while activity of 16-hydroxyl derivatives was weaker.Among 16-methylating compounds,the activity of 16-a substituted amide was stronger than corresponding 16-β substituted amide.