The Studies Of Several Types Of Natural Products On Reversal Tumor MDR And Anti-H1N1 Virus

This paper is composed of two parts.The first chapter is the research of natural products on reversing multidrug resistance of tumors in vitro,and the mechanism of dihydro-β-agarofuran sesquiterpenes and lathyrane diterpenoids as the modulators.The other chapter is the research of natural products on anti-influenza virus activities,and the anti-influenza A virus mechanism study of prenylated flavonoids in vitro.In this paper,172 natural products isolated from medicinal plants such as Tripterygium hypoglaucum,Euphorbia royleana,and Euphorbia lathyris were used to assay the activities about modulating the multi-drug resistance of tumors in vitro.The structural types included iridoids,sesquiterpenes,diterpenes,etc.Among them,we found a total of 32 compounds with potential activity,including dihydro-β-agarofuran sesquiterpenes,lathyrane diterpenoids,neo-clerodane diterpenoids and jatrophane diterpenoids.It is worth noting that 39（RF=456.9）,105（RF=448.39）and 133（RF=137.77）is significantly superior to verapamil（RF=94.24 times）,and the difference is statistically significant（p<0.05）.we chose 39,a dihydro-β-agarofuran sesquiterpene from Tripterygium hypoglaucum,for mechanism study.We found that 39 obviously inhibited the efflux of Dox（p<0.001）,but had no effect on the localization and expression of P-gp.The further results suggested that 39 significantly increased the activity of P-gp ATPase,improved the consumption of ATP（p<0.01）,and occupied PHE 979（h-PHE 983）,which was a key substrate binding site on P-gp.Summarily,we speculate that 39 may be a substrate of P-gp.In addition,we further studied the mechamism of 105.We found that 105increased the accumulation of Dox（p<0.001）,but had no effect on the expression and localization of P-gp.The further results suggested that 105 significantly improved the ATP consumption of P-gp（p<0.01）,and occupied PHE 339,which was a key substrate binding site on P-gp.We concluded that 105 may act by competitive binding to the substrate of P-gp in vitro.The anti-influenza A virus model was used to screen 152 segments from 37characteristic medicinal plants and 123 monomers isolated from Sophora flavescens,Euphorbia neriifolia,Swertia bimaculata and other medicinal plants.The structural types of the monomers involved in alkaloids,flavonoids,diterpenoids,triterpenoids and other types.The results indicated that the crude extracts from some plants had an obviously effect on influenza A virus,including the ethyl acetate（EA）phase of Pogostemon cablin(EC₅₀ 62.90μg/mL),Lonicera japonica(EC₅₀ 100.00μg/mL),Valeriana jatamansi(EC₅₀ 72.60μg/mL),Solanum nigrum L.(EC₅₀ 136.00μg/mL),and‘bandaoba’(EC₅₀ 42.40μg/mL),the butanol（E）phase of Rumex madaio(EC₅₀74.20μg/mL),Fagopyrum tataricum(EC₅₀ 140.00μg/mL)and Olea europaea(EC₅₀145.00μg/mL).Additionally,we found which are 17(EC₅₀ 23.90μM)and 21(EC₅₀43.90μM),22(EC₅₀ 38.10μM)and 25(EC₅₀ 32.00μM)with anti-influenza A activities,which were prenylated flavonoids and flavonoid glycosides.We investigated the mechanism of isopentenyl flavonoids 21 and 22 obtained from Sophora flavescens against influenza A virus.We found that 21 and 22 may exert anti-influenza effects through different mechanisms of action.Among them,22 can significantly reduce the expression of influenza virus NP in host cells during the process of virus entry,replication and release,and inhibit hemagglutinin agglutination,and influence the activity of the influenza virus surface antigen NA.While 21 may only target the influenza virus surface antigen NA.In addition,we found that 22 may be able to affect the function of host cell vesicle transport,and 21 does not have this effect.