Chemical Composition And Biological Activity Research Of Hypericum Elodeoides Choisy

Cancer has become one of the main diseases that endanger human health at present.The nuclear receptor RXRa is an ideal molecular target for antitumor drug development.In the previous research,some novel polycylic polyprenylated acylphloroglucinols(PPAPs)with RXRa transcriptional inhibition activity and cytotoxic activity were found from the plants of Hypericum sampsonii Hance.It is suggested that there are some PPAPs in Hypericum Linn,which may induce cancer cell apoptosis through RXRa pathway.Due to the limited type and quantity of isolated compounds,their mechanism and structure-activity relationship have not been clarified.Moreover,there is no systematic report on the chemical components of Hypericum as natural small molecule modulators which can induce tumor cell apoptosis through RXRa pathway.Our group have conducted literature research of the Hypericum plants in Fujian Province.It was found that Hypericum elodeoides Choisy was less studied,and its petroleum ether and dichloromethane extracts had RXR? transcriptional inhibition activities.In order to enrich the structural types of PPAPs as well as the chemical components of Hypericum plants,and discover the novel structural compounds that can regulate the RXRa signal pathway to induce tumor cells apoptosis,the chemical components and anti-tumor pharmacological activities of Hypericum were studied in this paper.Furthermore,the mechanism and structure-activity relationship of them were preliminarily discussed.In this study,73 compounds were isolated from the petroleum ether and dichloromethane extracts of H.elodeoides which soaked with 95%aqueous ethanol by silica gel column chromatography,ODS column chromatography,Sephadex LH-20 column chromatography and high-performance liquid chromatography.Their structures were elucidated by NMR,HRESI-MS,IR,UV,optical rotation,calculated ECD and modified Mosher's method.A total of 22 compounds were identified as unreported compounds,which were 1-20,25 and 30.Compounds 1-10 were polycylic polyprenylated acylphloroglucinols,11-24 were ring lactones,25-29 were chromones,30-34 were xanthones,35-36 were flavonoids,37 was an anthraquinone,38-41 were sesquiterpenoids,42 was a diterpenoid,43-44 were triterpenoids,45-47 were steroids,53-67 were fatty acids,48-52 and 68-73 were other types of compounds.Among the isolated PPAPs,1 was an unprecedented 1,6-seco monocyclic polyprenylated acylphloroglucinols(MPAPs)with fascinating 5/5 fused ring,2-4 were 1,2-seco MPAPs with a five-membered lactone core,5-7 were monoterpenoid polyprenylated acylphloroglucinols possessing 6/6/6 fused tricyclic core,8 was a dome-shaped polyprenylated phloroglucinol derivative possessing 6/5/5/5 fused tetracyclic core,9-10 were polyprenylated acylphlorogluciol derivatives possessing 6/5/5 fused tricyclic core.All compounds were reported for the first time in this plant.Compounds 21-24,26,27,29,31,33,35-38,40-47,49,51,53-59,61,63,65,68-70,72 were obtained for the first time in Hypericum,which enriched the structural types of chemical components of Hypericum.The cytotoxicity of the new isolates 1-20,25 and 30 toward HeLa cells was evaluated by the method of MTT colorimetry.It was found that compounds 1,5,7,25 and 30 showed obvious inhibitory effect on HeLa cell growth.Furthermore,the effects of compounds 1,5,7,25 and 30 on RXRa transactivation were examined by dual-luciferase reporter gene assay.The results showed that all the compounds exhibited concentration-dependent inhibitory effects of 9-cis-RA-induced RXRa transactivation.And compounds 1,5,7,25 and 30 were further studied by fluorescence quenching and Western blotting.The results suggested that the unreported compounds 7 and 30,which were isolated from Hypericum elodeoides,could potentially induce HeLa cell apoptosis through binding to the nuclear receptor RXR?,and compound 30 may trigger caspase-8 activation to induce cell apoptosis by the extrinsic pathways.Herein,the structure-activity relationship between the bioactivity compounds and RXR?-LBD protein was discussed by molecular docking.