一种新番荔枝内酯单体atemoyacin—B克服肿瘤多药抗药性

目的 探讨ａｔｅｍｏｙａｃｉｎ－Ｂ（Ａｔｅ）克服肿瘤多药抗药性（ＭＤＲ）作用及机制。方法 Ｂｕｌｌａｔａｃｉｎ（Ｂｕｌ）为阳性对照物,细胞毒测定以ＭＴＴ法,Ｐｇｐ功能测定以Ｆｕｒａ２－ＡＭ法,细胞内药物积累测定以荧光分光光度计法;细胞凋亡测定以流式细胞仪法,结果：Ａｔｅ对ＭＣＦ－７／Ｄｏｘ,ＭＣＦ－７,ＫＢＶ２００和ＫＢ细胞的ＩＣ５０分别为１２２,１２０,１．３４,１．２７ｍｍｏｌ．Ｌ＾－１,Ａｔ     

Biological activity of chemical constituents from <Emphasis Type="Italic">Clausena harmandiana</Emphasis>

The activity guided fractionation of the Clausena harmandiana root extracts led to the isolation of a coumarin, a ferulate, and eight carbazoles. This is the first report of the isolation of compounds 2–4 and 6–10 from this species, and this is the first time 10 was isolated from this genus. Compound 4 showed strong cytotoxicity against NCI-H187 cells with an IC₅₀ value of 1.63 μg/mL. Compound 5 demonstrated strong cytotoxicity against MCF-7 and KB cell lines with IC50 values of 2.21 and 1.74 μg/mL, respectively. Compounds 3 and 4 exhibited moderate cytotoxicity against the MCF-7 cell line, and 8 showed moderate cytotoxicity against NCIH187 and KB cell lines. Compounds 3 and 5 showed antiplasmodial activity with IC₅₀ values of 3.27 and 2.94 μg/mL, respectively.     

Rearranged <Emphasis Type="Italic">ent</Emphasis>-kauranes from the stems of <Emphasis Type="Italic">Tricalysia dubia</Emphasis> and their biological activities

From the EtOAc-soluble fraction of an MeOH extract of the stems of Tricalysia dubia, two new rearranged ent-kaurane derivatives, named tricalysiolides H and I, were isolated, together with five known rearranged ent-kauranes, i.e. tricalysiolides A–E, stigmast-4-en-6β-ol-3-one, (+)-pinoresinol, scopoletin and syringaldehyde. Their structures were elucidated from spectroscopic evidence, and their cytotoxicity toward KB cells and P-gp inhibitory activity were assayed.     

Biologically active <Emphasis Type="Italic">C</Emphasis>-alkylated flavonoids from <Emphasis Type="Italic">Dodonaea viscosa</Emphasis>

A new C-alkylated flavonoid (5,7-dihydroxy-3′-(4″-acetoxy-3″-methylbutyl)-3,6,4′-trimethoxyflavone (1), along with two known C-alkylated flavonoids (5,7-dihydroxy-3′-(3-hydroxymethylbutyl)-3,6,4′-trimethoxyflavone (2), 5,7,4′-trihydroxy-3′-(3-hyroxymethylbutyl)-3,6-dimethoxyflavone (3) and two new source C-alkylated flavonoids (5,7-dihydroxy-3′-(2-hydroxy-3-methyl-3-butenyl)-3,6,4′-trimethoxyflavone (4), 5,7,4′-trihydroxy-3,6-dimethoxy-3′-isoprenyl-flavone (5) were isolated from the aerial parts of Dodonaea viscosa. The structures of all compounds were established on the basis of 1D and 2D NMR spectroscopy and mass spectrometry. The isolated compounds were evaluated for their inhibitory effect on urease and α-chymotrypsin enzyme. All the compounds (1–5) exhibited mild inhibition against urease but remained recessive in case of α-chymotrypsin.     

Anti-inflammatory phenylpropanoid glycosides from <Emphasis Type="Italic">Clerodendron trichotomum</Emphasis> leaves

The chromatographic separation of MeOH extract from Clerodendron trichotomum Thunberg leaves led to the isolation of three phenylpropanoid compounds. Using spectroscopic methods, the structures of these compounds were determined as β-(3′, 4′-dihydroxyphenyl)ethyl-O-α-L-rhamnopyranosyl (1→3)-β-D-(4-O-caffeoyl)-glucopyranoside, acteoside (verbascoside) (1), β-(3′, 4′-dihydroxyphenyl)ethyl-O-α-L-rhamnopyranosyl (1→3)-β-D-(6-O-caffeoyl)-glucopyranoside, isoacteoside (2), β-(3′, 4′-dihydroxyphenyl) ethyl-O-α-L-rhamnopyranosyl (1→3)-β-D-glucopyranoside, and decaffeoylacteoside (3). We measured the anti-inflammatory activity of these three phenylpropanoid compounds both in vitro (DPPH Reduction Assay, TBARS Assay on Cu ²⁺-induced oxidized LDL, PGE₂ assay) and in vivo (acetic acidinduced vascular permeability in mice and carrageenan-induced hind paw edema in rats). 80% methanol fraction and acteoside had the activity.     

Phenolic constituents of <Emphasis Type="Italic">Acorus gramineus</Emphasis>

The purification of a MeOH extract from the rhizome of Acorus gramineus (Araceae) using column chromatography furnished two new stereoisomers of phenylpropanoid, acoraminol A (1) and acoraimol B (2). It also furnished 17 known phenolic compounds, β-asarone (3), asaraldehyde (4), isoacoramone (5), propioveratrone (6), (1′R,2′S)-1′,2′-dihydroxyasarone (7), (1′S,2′S)-1′,2′-dihydroxyasarone (8), 3′,4′-dimethoxycinnamyl alcohol (9), 3′,4′,5′-trimethoxycinnamyl alcohol (10), kaempferol 3-methyl ether (11), 2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-1,3-propanediol (12), hydroxytyrosol (13), tyrosol (14), (2S,5S)-diveratryl-(3R,4S)-dimethyltetrahydrofuran (15), (7S,8R)-dihydrodehydrodiconiferyl alcohol (16), 7S,8S-threo-4,7,9,9′-tetrahydroxy-3,3′-dimethoxy-8-O-4′-neolignan (17), 7S,8R-erythro-4,7,9,9′-tetrahydroxy-3,3′-dimethoxy-8-O-4′-neolignan (18), and dihydroyashsbushiketol (19). The structures of the new compounds were elucidated by analysis of spectroscopic data including 1D and 2D NMR data. The absolute configurations of 1 and 2 were determined using the convenient Mosher ester procedure. Compounds 5–19 were isolated for the first time from this plant source. The isolated compounds were tested for cytotoxicity against four human tumor cell lines in vitro using a Sulforhodamine B (SRB) bioassay.     

Cholinesterase inhibitors from <Emphasis Type="Italic">Cleistocalyx operculatus</Emphasis> buds

Five flavonoids, myricetin-3′-methylether 3-O-β-d-galactopyranoside (1), myricetin-3′,5′-dimethylether 3-O-β-d-galactopyranoside (2), quercetin (3), kaempferol (4), and tamarixetin (5) were isolated from the buds of Cleistocalyx operculatus (Myrtaceae). The chemical structures of these compounds were determined on the basis of spectroscopic analyses, including 2D NMR. Their anti-Alzheimer effects were evaluated via acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity assays. All five compounds 1–5 showed potential inhibitory activities against AChE with IC₅₀ values of 19.9, 37.8, 25.9, 30.4 and 22.3 μM, respectively, while compounds 1, 3, 4 and 5 also possessed BChE inhibitory activity with IC₅₀ values of 152.5, 177.8, 62.5, and 160.6 μM, respectively.     

Lignans from the flowers of <Emphasis Type="Italic">Osmanthus fragrans</Emphasis> var. <Emphasis Type="Italic">aurantiacus</Emphasis> and their inhibition effect on NO production

A new lignan, (7R,7′R,8R,8′R)-8-hydroxypinoresinol 8-O-β-D-glucopyranoside 4′-methyl ether (7), was isolated from the flowers of Osmanthus fragrans var. aurantiacus along with six known lignans: (+)-phillygenin (1), phillyrin (2), (−)-phillygenin (3), (−)-epipinoresinol-β-D-glucoside (4), taxiresinol (5), and (−)-olivil (6). The structure of the new compound was elucidated on the basis of 1D- and 2D-NMR spectroscopic analysis and specific rotation data. The compounds isolated from the flowers of O. fragrans var. aurantiacus were evaluated for inhibitory activities on nitric oxide production in lipopolysaccharide-stimulated macrophage RAW 264.7 cells. (+)-Phillygenin (1), phillyrin (2), and (−)-phillygenin (3) exerted the strongest inhibitory activities on NO production with IC₅₀ values of 25.5, 18.9, and 25.5 μM, respectively. These compounds may prove beneficial in the development of natural agents for prevention and treatment of inflammatory diseases.     

Chemical and biologically active constituents of <Emphasis Type="Italic">Pteris multifida</Emphasis>

A new compound, 4-caffeoyl quinic acid 5-O-methyl ether (2), together with 12 known compounds—identified as (2R,3R)-pterosin L 3-O-β-d-glucopyrannoside (3), β-sitosterol β-d-glucopyranoside (4), apigenin 7-Ο-β-d-glucopyranoside (5), luteolin 7-Ο-β-d-glucopyranoside (6), sucrose (7), caffeic acid (8), pterosin C 3-Ο-β-d-glucopyranoside (9), pteroside C (10), 4,5-dicaffeoyl quinic acid (11), pteroside A (12), wallichoside (13) and (2S)-5,7,3′,5′-tetrahydroxyflavanone (14)—were isolated from Pteris multifida. The structure of the new compound was determined by means of physical, chemical and spectroscopic evidence. Compounds 5 and 6 were the main constituents of the plant, with yields of 0.19% and 0.16%, respectively. The cytotoxic activities of 2, 3, and 9–13 were evaluated against a human cell line (KB cells). Among the isolated compounds, pterosin C 3-Ο-β-d-glucopyrannoside (9) and 4,5-dicaffeoylquinic acid (11) showed a significant selective cytotoxicity (IC₅₀ 2.35 and 5.38, respectively), while moderate activity was observed for compound 2 (IC₅₀ 12.3). The chemosystematics of Pteris species is also discussed.     

A new phenolic glycoside syringate from the bark of <Emphasis Type="Italic">Juglans mandshurica</Emphasis> MAXIM. var. <Emphasis Type="Italic">sieboldiana</Emphasis> MAKINO

A new phenolic glycoside syringate, 4′-hydroxy-2′,6′-dimethoxyphenol 1-O-β-d-(6-O-syringoyl) glucopyranoside (1), together with two known ones, 2′-hydroxy-4′-methoxyphenol 1-O-β-d-(6-O-syringoyl) glucopyranoside (2) and 4′-hydroxy-2′-methoxyphenol 1-O-β-d-(6-O-syringoyl) glucopyranoside (3), were isolated from the bark of Juglans mandshurica MAXIM. var. sieboldiana MAKINO. Their structures were established on the basis of spectral and chemical data.     

Potential anthelmintics: polyphenols from the tea plant <Emphasis Type="Italic">Camellia sinensis</Emphasis> L. are lethally toxic to <Emphasis Type="Italic">Caenorhabditis elegans</Emphasis>

A novel gallate of tannin, (−)-epigallocatechin-(2β→O→7′,4β→8′)-epicatechin-3′-O-gallate (8), together with (−)-epicatechin-3-O-gallate (4), (−)-epigallocatechin (5), (−)-epigallocatechin-3-O-gallate (6), and (+)-gallocatechin-(4α→8′)-epigallocatechin (7), were isolated from the tea plant Camellia sinensis (L.) O. Kuntze var. sinensis (cv., Yabukita). The structure of 8, including stereochemistry, was elucidated by spectroscopic methods and hydrolysis. The compounds, along with commercially available pyrogallol (1), (+)-catechin (2), and (−)-epicatechin (3), were examined for toxicity towards egg-bearing adults of Caenorhabditis elegans. The anthelmintic mebendazole (9) was used as a positive control. Neither 2 nor 3 were toxic but the other compounds were toxic in the descending order 8, 7 ≈ 6, 9, 4, 5, 1. The LC₅₀ (96 h) values of 8 and 9 were evaluated as 49 and 334 μmol L⁻¹, respectively. These data show that many green tea polyphenols may be potential anthelmintics.     

A new acyclic diterpene acid and bioactive compounds from <Emphasis Type="Italic">Knema glauca</Emphasis>

Investigation of the chemical constituents of the fruits of Knema glauca (Myristicaceae) yielded a new acyclic diterpene acid, named glaucaic acid 4, together with four acylphenols, including 1-(2,6-dihydroxyphenyl) tetradecan-1-one 1, malabaricone A 6, dodecanoylphloroglucinol 7 and 1-(2,4,6-trihydroxyphenyl)-9-phenylnonan-1-one 8, two lignans sesamin 2 and asarinin 3, and a flavan, myristinin D 5. In addition, myristinin A 9 and (±)-7,4′-dihydroxy-3′-methoxyflavan 10 were isolated from its leaves and stems, respectively. When tested against small-cell lung cancer (NCI-H187), epidermoid carcinoma (KB) and breast cancer (BC) cell lines, compounds 1, 6–8 and 10 displayed weak to moderate cytotoxicity. The acylphenols 6–8 displayed antituberculosis activity against the microbe Mycobacterium tuberculosis with MIC values of 25, 50 and 100 μg/mL, respectively, and antiviral activity against herpes simplex virus type 1, with 7 as the most active compound (IC₅₀ = 3.05 μg/mL). Malabaricone A 6 was also active against the malarial parasite Plasmodium falciparum with an IC₅₀ value of 2.78 μg/mL.     

Construction of a Functional Transporter Analysis System Using <Emphasis Type="BoldItalic">MDR1</Emphasis> Knockdown Caco-2 Cells

Purpose The efflux transporter, P-glycoprotein (P-gp), located in the brush-border membrane of intestinal absorptive cells, reduces the bioavailability of a wide range of orally administered drugs. Using P-gp inhibitors in transport experiments in Caco-2 cell monolayers is widely accepted as an efficient way to estimate the contribution of P-gp to the intestinal absorption of drugs. However, there still remain some arguments that the inhibitors might affect the function of other proteins. Multidrug resistance 1 gene (MDR1) specifically inhibited Caco-2 cells were constructed, therefore, as a better in vitro evaluation system of intestinal drug absorption.Methods The effective sites of RNAi were selected using siRNA libraries and single siRNAs and MDR1 stable knockdown Caco-2 cells were constructed using a tRNA^val-shRNA expression vector.Results In siRNA stably expressed Caco-2 cells, the expression level of MDR1 was reduced at mRNA and protein levels. Transcellular transport studies using digoxin revealed that the P-gp function was suppressed completely, similar to that in verapamil-treated cells.Conclusions MDR1 stable knockdown Caco-2 cells were successfully constructed by RNAi technology. This will consequently allow the development of a selection system for candidate drugs with improved absorption properties.     

Hydroxyespintanol and schefflerichalcone: two new compounds from <Emphasis Type="Italic">Uvaria scheffleri</Emphasis>

A chemical investigation of the petroleum ether extract and chloroform extract of the root of Uvaria scheffleri Diels (Annonaceae) led to the isolation of two new compounds, named hydroxyespintanol (1) and schefflerichalcone (2), together with eight known compounds (3–10). The structural elucidation of compounds 1 and 2 by spectroscopic studies is described. The cytotoxicity of the isolated compounds against human promyelocytic leukemia HL-60 cells was studied. Among these, 2′-hydroxy-3′,4′,6′-trimethoxychalcone (5) exhibited cytotoxicity (IC₅₀ 12 μM), and espintanol (3), which was the main ingredient, also showed some cytotoxicity (IC₅₀ 44 μM).     

Experimental studies on the lead accumulation in the cestode <Emphasis Type="Italic">Moniezia</Emphasis><Emphasis Type="Italic">expansa</Emphasis> (Cestoda: Anoplocephalidae) and its final host (<Emphasis Type="Italic">Ovis aries</Emphasis>)

The tapeworm Moniezia expansa and naturally infected sheep were investigated with respect to their lead accumulation. Lead—Pb(CH₃COO)₂ was added to the distilled water and administered orally to the sheep every day for a period of 1 week. After the exposure period the sheep were killed and the metal levels were determined in the muscle, liver, kidney and blood of the sheep as well as in the cestode parasites (Moniezia expansa). The impact of an infection with the cestode Moniezia expansa and a simultaneous Pb exposure, on the concentrations of heavy metals in the host kidney, liver, muscle, blood and cestodes was studied. The concentration of lead in the cestodes was on average 458, 5 and 4-fold higher in the cestodes than in the muscle, liver and kidney of the host, respectively. Parasitised sheep accumulated significantly less lead in their tissues than their uninfected conspecifics (ANOVA test, P ≤ 0.05). Also the differences between host′s tissues and tapeworms were found to be significant (ANOVA test, P ≤ 0.05). Thus, this study reveals that lead accumulation also occurs in cestodes parasitizing mammals. The host-parasite-system sheep-Moniezia expansa appears to be a useful and promising bioindication system especially in farming (rural, agricultural) and the natural ecosystem.     

Effect of <Emphasis Type="Italic">MDR1</Emphasis> C3435T polymorphism on lansoprazole in healthy Japanese subjects

Background and aims  The effect of multidrug resistance transporter gene 1 (MDR1) on the bioavailability and kinetics of several substrates has not yet been fully elucidated. We evaluated the influence of MDR1 C3435T polymorphism on the pharmacokinetics and pharmacodynamics of lansoprazole in Japanese subjects. Methods  Fifteen healthy volunteers with the rapid extensive metabolizer genotype of CYP2C19 were classified into three MDR1 C3435T genotype groups: C/C (n = 5), C/T (n = 5), and T/T (n = 5). Lansoprazole 30 mg was administered orally for 15 days. The intragastric pH and plasma lansoprazole levels were determined on days 1 and 15. Results  On day 1, the mean C_max of lansoprazole in the T/T group was significantly higher than that in the C/C or C/T groups (T/T 1,248, C/C 618, C/T 607 ng/ml; P = 0.038). On day 15, similar MDR1 genotype-dependent differences were observed in the C_max of lansoprazole, although smaller than the differences observed on day 1. In contrast, the intragastric pH attained after lansoprazole administration did not differ among MDR1 genotype groups on either day 1 or day 15. Conclusion  Although the sample size was small, our study demonstrated that the MDR1 C3435T polymorphism influenced the pharmacokinetics, but not the pharmacodynamics (i.e., intragastric pH), of lansoprazole in rapid metabolizers of CYP2C19.     

Solalyratins A and B,new anti-inflammatory metabolites from <Emphasis Type="Italic">Solanum lyratum</Emphasis>

A new coumestan (solalyratin A, 1) and a novel cyclic eight-membered α,β-unsaturated ketone (solalyratin B, 3), together with three known compounds, puerariafuran (2), coumestrol (4) and 9-hydroxy-2′,2′-dimethylpyrano[5′,6′:2,3]-coumestan (5), were isolated from the whole plant of Solanum lyratum. Their structures were elucidated on the basis of spectroscopic analyses. In vitro, compounds 1–5 showed anti-inflammatory activities, with IC₅₀ values in the range 6.3–9.1 μM.     

Prenylated flavones from <Emphasis Type="Italic">Artocarpus altilis</Emphasis>

Six prenylated flavones, including one new compound, were isolated and identified from the stem bark extracts of Artocarpus altilis. The new prenylated flavone hydroxyartocarpin (1) was characterized as 3-(γ,γ-dimethylallyl)-6-isopentenyl-5,8,2′,4′-tetrahydroxy-7-methoxyflavone and the known compounds were artocarpin (2), morusin (3), cycloartobiloxanthone (4), cycloartocarpin A (5) and artoindonesianin V (6). The structures of the compounds were determined by spectroscopic methods (IR, MS, ¹H-NMR and ¹³C-NMR) and comparison with published data for the known compounds.     

New flavonoids with 2BS cell proliferation promoting effect from the seeds of <Emphasis Type="Italic">Trigonella foenum</Emphasis>-<Emphasis Type="Italic">graecum</Emphasis> L.

Ten flavonoids were isolated from the ethyl acetate-soluble fraction of the ethanolic extract of the seeds of Trigonella foenum-graecum and their structures were elucidated on the basis of spectroscopic methods to be 5,7,3′-trihydroxy-5′-methoxylisoflavone (1), biochanin A (2), formononetin (3), irilone (4), tricin (5), daidzein (6), calycosin (7), orientin-2″-O-p-trans-coumarate (8), vitexin-2″-O-p-trans-coumarate (9), and tricin-7-O-β-d-glucopyranoside (10). Compounds 1 and 8 are new flavonoids, and 8 and 9 strongly promoted 2BS cell proliferation induced by H₂O₂.     

Phenylpropanoid glycosides from <Emphasis Type="Italic">Heterosmilax erythrantha</Emphasis> and their antioxidant activity

By various chromatographic methods, one new phenylpropanoid glycoside, heterosmilaside (1), two known phenylpropanoid glycosides, helonioside B (2), and 2′,6′-diacetyl-3,6-diferuloyl sucrose (3), and three known flavonoids, isoquercetin (4), quercetin-3-O-β-D-glucuronopyranoside (5), and quercetin-3-O-(2″-α-L-rhamnopyranosyl)-β-D-glucuronopyranoside (6) were isolated from the methanolic extract of the aerial part of Heterosmilax erythrantha Baill. Their structures were elucidated on the basis of spectroscopic analyses. All the isolated compounds were tested for antioxidant activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay. Among them, compounds 5 and 6 showed significant antioxidant activity with SC₅₀ values of 3.7 and 6.5 μg/mL, respectively.