Anti-inflammatory Chalcone Dimers And Chalcone-isoflavonoid Dimers From Caragana Jubata

The genus Caragana belongs to the family of Leguminosae.There are more than 100 species all over the world,which distributed in Asia and the semi-dry areas of Europe.Modern pharmacological activities of Caragana species include anti-tumor,anti-inflammatory,anti-viral,antioxidant,and anti-hypertensive activities.Caragana jubata(pall.)Poir.,the main original plant of Tibetan medicine Lignum Caraganae is a perennial thorny shrub with light red or nearly white flowers of the Leguminosae family which is commonly found in the harsh alpine shrubbery.The plant is distributed naturally throughout the northern and southwest areas of China’s mainland and the Siberia of Russia,Mongolia,and Central Asia.The red heartwoods of the rhizomes of C.jubata are considered to have ’promoting blood circulation,inhibiting blood stasis,and lowering blood pressure’ functions and have been applied commonly to the treatment of ischemic cardiovascular and cerebrovascular diseases(ICCD),polycythemia,hypertension and menstrual disorders when compounded with other herbal medicines.Previous phytochemical studies of C.jubata have led to the isolation of flavonoids,stilbenes,terpenoids,sterols,and several other kinds of compounds.There is no reporton the chalcone dimers and chalcone-isoflavone dimers from the genus Caragana.In this dissertation,the varieties,the chemical structures,the pharmacological activities,and the plausible biosynthetic pathways of the chalcone dimers and chalcone-isoflavone dimers have been summarized.The studies of this dissertation include the phytochemistry research of the dichloromethane extract from Caragana jubata,structural elucidation of the new compounds,study on the anti-inflammatory activities of the chalcone dimers and chalcone-isoflavonoid dimers and study of the biosynthetic pathways of the new compounds.Two new chalcone-isoflavone derivatives,caraganins A(1)and B(2),two new dimeric chalcone derivatives,caraganins C(3)and D(4),together with two known compounds(5-6)and two unidentified componds(7-8)were isolated from the red heartwood of the rhizome of Caragana jubata.The chemical structures of 1-4 were elucidated based on 1D and 2D NMR spectroscopic,HRMS,and ECD analysis and comparison with reported data.The C-C linked mode of compounds 1 and 2 which the B ring of a isoflavonoid linked with a diphenyl propylene was found for the first time.The potential anti-inflammatory activities of new compounds were evaluated subsequently by measuring lipopolysaccharide(LPS)-induced nitric oxide(NO)formation,expression of tumor necrosis factor alpha(TNF-α)and interleukin-6(IL-6)in murine RAW 264.7 macrophages.Among these,compounds 2 and 4 exhibited the most potent inhibitory activities(IC50:4.09 and 5.21 μM,respectively)to NO formation;and compounds 1 and 4 showed the most promising inhibitory activities,with IC50 values of 11.37 and 14.72 μM against the production of inflammatory factor TNF-α.The possible biosynthesis pathways of the chalcone-isoflavone and the dimeric chalcone derivatives are discussed according to the literatures.The plausible biosynthetic pathways of the chalcone-isoflavonoids dimers 1 and 2 might via the addition reaction of α,β-unsaturated by the iso-flavonoid attacking the β-carbon or the carbonyl carbon of the chalcone,and via the following reduction reaction to form the compound 1 and 2.The plausible biosynthetic pathways of the chalcone dimers 3 and 4 might via reduction and dehydration reaction of the chalcone to form a intermediate compound.And then the intermediate and the chalcone convert to the compound 3 via[4+2]cycloaddition,and reduction reactions,or the intermediate and another chalcone convert to the compound 4 via[4+2]cycloaddition,nucleophilic substitution and reduction reactions.