Studies On The Secondary Metabolites And Their Bioactivities Of Valeriana Jatamansi

Valeriana jatamansi Jones originally recorded in an ancient article,Southern Yunnan Materia Medica,and named"Zhizhuxiang"because of its spider-like observation,which has thick main roots and surrounding fibrous roots with fragrant smell.V.jatamansi is a well-known traditional Chinese medicine.Its mainly roots and stems have been used for the treatment of various diseases,such as sleep problems,nervous disorders,epilepsy,and so on.Previous literature reported that numerous isolated iridoids from V.jatamansi exhibited promising cytotoxic and anti-cancer effects.Additionally,V.jatamansi has been used for treating flu diseases that demonstrated in the literature of Chinese Materia Medica and Yunnan Materia Medica.The isolated components,valtrate,isovaltrate and isovaltrate acetoxyhydrin showed anti-influenza virus activity.Our preliminary study screened 227 crude extracts from 37 medicinal plants for their activities against the influenza virus.The ethyl acetate extract of V.jatamansi showed anti-influenza A virus activity.800 crude components of 60 medicinal plants also were screened for their anti-glioma stem cells.The results indicated that the two crude components of V.jatamansi inhibited glioma stem cells selectively.Based on the above study,a systematic study on the chemical composition and biological activity of V.jatamansi was investigated.One-hundred twenty-three compounds,including 63 new compounds and two novel compounds discovered at the first time in nature,were isolated from the Et OAc-soluble fraction of the roots and rhizomes of V.jatamansi.Their structures were elucidated by 1D NMR,2D NMR,HR-ESI-MS,and MS spectroscopic data,quantum chemical calculation,and comparison of their spectroscopic data with literature values.Among them,the structural types of isolated compounds consist of95 for iridoids,5 for sesquiterpenes,11 for lignans,two for steroids,and 10 for other types of compounds.Iridoids are the main component of V.jatamansi,including bis-iridoids,3,8-epoxy iridoids,monoene iridoids,diene iridoids,and seco-iridoids.The lignans also have higher content in V.jatamansi,mainly ditetrahydrofuran-type lignans.Compounds 1?5 were the first report of bis-iridoids isolated from V.jatamansi.Jatamansidoids A-G（34?41）are the first examples of iridoids from V.jatamansi with unique?,?,?,?-unsaturated aldehyde fragment between C-11,C-4,C-5,C-8 and C-9.Jatamansidoid H（42）is an unprecedented iridoid derivative with a methyl group（Me-10）at C-1,rather than C-8.Jatamansidoid N（62）,jatamansidoid O（63）and jatavaleridoid G（64）are the first examples of?^4（5）-iridoids simultaneously replaced by oxygen-containing groups at C-3,C-6 and C-7.Jatamansidoid Q（65）is the first iridoid with both 6,7-and 1,10-epoxy fragments.The C-10 positions of compounds 11,45?48 and 51 are all substituted by long-chain fatty acid esters.Such iridoids are rarely found in V.jatamansi,and only one has been reported in the literature.Compounds 86 and 87 are the first seco-iridoids with their C-1 and 2-O openings,and 2-O and C-6 are connected to form a new ring.Compound 88?92 are the first seco-iridoids with a conjugated system in C-3,C-4,C-5,C-6,and C-7.Compounds 95?97 are the norsesquiterpenes isolated from this plant for the first time.The results of bioactivities screening indicated that compounds 52,55,56,98,99and 100 exhibited significant effects against A/Puerto Rico/8/1934（H1N1）,with IC₅₀values of 0.21,1.40,1.31,1.48,1.30 and 0.30μM,respectively.Furthermore,compounds 52 and 55 exhibited potent activity against VR1679（H3N2）virus,with IC₅₀ values of 0.20 and 1.76μM,respectively.In addition,compounds 17 and 21displayed significant inhibition of NO production with IC₅₀values of 4.62 and 15.80?M,respectively(positive control L-NMMA,IC₅₀=21.80μM).Therefore,iridoids and patchoulol-type sesquiterpenoids are critical active constituents of V.jatamansi to exert anti-influenza virus effects.Compounds 21,80,84 and 95 showed selective cytotoxic potency against GSC-3#,GSC-12#,and GSC-18#glioma stem cells with IC₅₀values ranging from 12.76 to 61.76μM,while compound 17 selectively inhibited GSC-18#glioma stem cell growth.Compound 5 showed weak inhibition against GSC-3#,GSC-12#and GSC-18#.Compound 21 could inhibit GSCs proliferation and induce apoptosis.Furthermore,compound 21 inhibited the ability of GSC colony formation,indicating its antitumor activity against human glioma stem cells.In summary,123 compounds were obtained from V.jatamansi,including 63 new compounds and two new natural products.Six compounds with significant anti-influenza activity,six with selective inhibition of glioma stem cells,and three with inhibition of nitric oxide production were found by biological activity study.Our study clarified the material basis of V.jatamansi for the treatment of flu.Monoene iridoids were found to possess anti-oseltamivir-resistant influenza virus activity for the first time.Furthermore,bis-iridoids and 3,8-epoxy iridoids were found to have selective anti-glioma stem cells for the first time.This present research systematically discovered the chemical components and biological activities of V.jatamansi and established the structure-activity relationship of the isolated compounds,particularly in the investigation of iridoids and patchoulol-type sesquiterpenoids.This investigation contributes to the drug development of anti-influenza virus drugs by providing a robust approach for further structural modification,structure-activity relationship analysis,and mechanism study.