Study On The Synthesis And Structure-activity Relationship Of Ionone Alkaloid Derivatives

Objective The previous study found that ionone alkaloid,pachysandramine A had significant anti-metastasis activity against breast cancer cells.Based on this lead compound,two series of racemic and chiral ionone alkaloid derivatives were designed and synthesized.This paper deals with the anti-metastasis activities and structure-activity relationship of ionone alkaloid derivatives.Methods The racemic ionone alkaloid derivatives were prepared by reductive amination,haloform reaction,amidation reaction,amide reduction reaction,allylic oxidation,amino protection and de-protection,and substitution nucleophilic reaction from?-ionone as starting material.The chiral ionone alkaloid derivatives were prepared through chiral resolution and multi-step reactions.The chemical structures of all target compounds have been characterized by spectroscopic methods.The structure-activity relationship was studied based on their anti-metastatic activities evaluated by invasion assay.Results 1.One hundred and twenty-five compounds,including thirty two intermediates and ninety three derivatives,were synthesized by organic chemistry reactions.All of the compounds were identified by spectroscopic methods.The synthesized derivatives were new compounds which had not been reported before.2.The MTT assay was used for evaluation of the cytotoxicity of derivatives,andthe derivatives showed no cytotoxicity in the concentrations from 0.25 to 25?M.The derivatives were screened by invasion assay in MDA-MB-231 cells under non-cytotoxic concentrations.The results showed that compounds 4i,4j,27b,28b,30a,31a,32a,35b,and 36a revealed significant anti-metastasis activity,and their IC₅₀values are in the range from 0.016 to 1.067?M,comparing with the positive control,LY294002(IC₅₀=1.18?M).3.The structure-activity relationship study on the racemic ionone alkaloid derivatives had indicated that tertiary amine significantly affected the anti-metastatic activities.When N,N-dimethyl group or fluoro benzene group was existed,the activities of derivatives were significantly improved.Meanwhile,the chiral center of ionone ring C-6 exerted an important role in response to the anti-metastatic activity.The structure-activity relationship study of chiral ionone alkaloid derivatives indicated that the chiral center of ionone ring C-6 and the substituted pattern of fluoro benzene group significantly affected the anti-metastatic activity.As for7,8-dihydro ionone alkaloid derivatives,it is notably that the R-enantiomer compounds exhibited much stronger potencies than those of S-enantiomers.The m-fluoro substituted R-enantiomer exhibited the strongest activity.On the other hand,in the 7-ene ionone alkaloid quaternary ammonium derivatives,the p-fluoro substituted S-enantiomer exhibited the strongest activity.4.Compounds 31a and 35b down regulated the expression of p-integrin?1 and p-PKC?in a dose-dependent manner.Compounds 31a and 35b might exhibit the anti-metastatic activity via suppressing the expressions of p-PKC?and p-integrin?1.Conclusion In this paper,two series of new ionone alkaloid derivatives were synthesized through multi-step organic reactions from?-ionone as starting material.Compounds 4i,4j,27b,28b,30a,31a,32a,35b and 36a exhibited significant inhibitory effects on the invasion of human MDA-MB-231 breast cancer cells.The structure-activity relationship indicated that the chiral center of ionone ring C-6exerted an important role in response to the anti-metastatic activity.When N,N-dimethyl group or fluoro benzene group was existed,the activities of derivatives were significantly improved.Compounds 31a and 35b might exhibit the anti-metastatic activity via suppressing the expressions of p-PKC?and p-integrin?1.