Synthesis And Biological Activities Determination Of ButyrolactoneⅠ And Majusculoic Acid Derivatives

Most of the natural products have unique pharmacological activities.Pharmacological molecules can be identified by scientists through extraction and purification of natural products as well as chemical synthesis.Butyrolactone I was the secondary metabolites of the fungus Aspergillus,which has several biological activities.It has three hydroxyl groups and a neoprenyl group.The pharmacological activities of butyrolactone I are mainly about anti-tumor,anti-virus,type II diabetes improvement and anti-food allergy activity.There are relatively few researches about the anti-allergic activity of butyrolactone I.The structure and activity relationship of butyrolactone I in anti-food allergy activity would be illucidated in this research.And majusculoic acid is a fatty acid derived from cyanobacteria which has 15 carbon atoms.It has a specific trans-cyclopropane and a brominated conjugated diene structure in the molecule,and performing inhibitory effect on the growth of Candida albicans.However,the potential anti-inflammatory activity of those compounds and the structure activity relationship of them remain unknown.In order to solve those problems,we conducted researches on the derivatization of butyrolactone I and majusculoic acid,as well as identification of related pharmacological activities:1.Butyrolactone I can be obtained from the fermentation of the fungus Aspergillus terreus 768 through extraction and purification,and then modifying its structure based on the strategy of "multiple synthetic derivatization".The modification derivatives mainly included hydroxyl groups,neoprenyl and ester groups modified products.Then the anti-allergic activity of butyrolactone I derivatives were determined by RBL-2H3 cells.We synthesized 18 butyrolactone I derivatives through diverse synthesis strategy,and determination of the structure-activity relationship of butyrolactone I in anti-allergic activity.At the same time,we had found one compound that inhibited the degranulation of RBL-2H3 cells.The allylated compound showed the same inhibitory activity as butyrolactone I.The significance of our research is to determine the structure-activity relationship of the anti-allergic activity of butyrolactone I,which could help to identify a better modification product of butyrolactone I in the future.2.Majusculoic acid and other seven derivatives can be synthesized by HWE reaction.We designed those analogues guided by the strategy of “simplifying structure derivatization”.Those simplified structures included halogen atom deletion,fatty acid esterification,carbon chain shortening,and cyclopropane deletion.We applied the LPS-induced mouse macrophage(RAW264.7)inflammation model to explore the structure-activity relationship of majusculoic acid derivatives.The results of anti-inflammatory activity revealed that majusculoic acid,methyl ester of majusculoic acid and the carbon chain shortened ethyl ester have dose-dependent anti-inflammatory activity.Majusculoic acid and its methyl ester are not cytotoxic in cell proliferation by CCK-8 test.Having realized the synthesis of over 18 butyrolactone I analogues,and evaluating the anti-allergic bioactivity of them.And we also realized the total synthesis of majusculoic acid and its analogues,and anti-inflammatory activity determination.The structure and activity relationship of those two types of compounds were clarified in our research.