RESUMO
Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715, a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in normotensive Sprague-Dawley rats.
Assuntos
Ácidos Carboxílicos/química , Glucuronídeos/química , Hipertensão Pulmonar/tratamento farmacológico , Guanilil Ciclase Solúvel/metabolismo , Vasodilatadores/química , Administração Oral , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Glucuronídeos/administração & dosagem , Glucuronídeos/farmacocinética , Humanos , Masculino , Metaboloma , Modelos Moleculares , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Ratos Sprague-Dawley , Transdução de Sinais , Relação Estrutura-Atividade , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacocinéticaRESUMO
Curcumin, a major polyphenol present in turmeric, is predominantly converted to curcumin-O-glucuronide (COG) in enterocytes and hepatocytes via glucuronidation. COG is a principal metabolite of curcumin in plasma and feces. It appears that the efflux transport of the glucuronide conjugates of many compounds is mediated largely by multidrug resistance-associated protein (MRP) 3, the gene product of the ATP-binding cassette, subfamily C, member 3. However, it is currently unknown whether this was the case with COG. In this study, Mrp3 knockout (KO) and wild-type (WT) mice were used to evaluate the pharmacokinetics profiles of COG, the liver-to-plasma ratio of COG, and the COG-to-curcumin ratio in plasma, respectively. The ATP-dependent uptake of COG into recombinant human MRP3 inside-out membrane vesicles was measured for further identification, with estradiol-17ß-d-glucuronide used in parallel as the positive control. Results showed that plasma COG concentrations were extremely low in KO mice compared with WT mice, that the liver-to-plasma ratios of COG were 8-fold greater in KO mice than in WT mice, and that the ATP-dependent uptake of COG at 1 or 10 µM was 5.0- and 3.1-fold greater in the presence of ATP than in the presence of AMP, respectively. No significant differences in the Abcc2 and Abcg2 mRNA expression levels were seen between Mrp3 KO and WT mice. We conclude that Mrp3 is identified to be the main efflux transporter responsible for the transport of COG from hepatocytes into the blood. SIGNIFICANCE STATEMENT: This study was designed to determine whether multidrug resistance-associated protein (Mrp) 3 could be responsible for the efflux transport of curcumin-O-glucuronide (COG), a major metabolite of curcumin present in plasma and feces, from hepatocytes into the blood using Mrp3 knockout mice. In this study, COG was identified as a typical Mrp3 substrate. Results suggest that herb-drug interactions would occur in patients concomitantly taking curcumin and either an MRP3 substrate/inhibitor or a drug that is predominantly glucuronidated by UDP-glucuronosyltransferases.
Assuntos
Curcumina/análogos & derivados , Glucuronídeos/farmacocinética , Hepatócitos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Administração Oral , Animais , Curcumina/administração & dosagem , Curcumina/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Estradiol/farmacocinética , Glucuronídeos/administração & dosagem , Masculino , Camundongos , Camundongos Knockout , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genéticaRESUMO
The traditional antimalarial herb Artemisia annua L., from which artemisinin is isolated, is widely used in endemic regions. It has been suggested that artemisinin activity can be enhanced by flavonoids in A. annua; however, how fast and how long the flavonoids are present in the body remains unknown. In the present study, a rapid and sensitive liquid chromatography with tandem mass spectrometry method was developed and validated for the simultaneous determination of three major flavonoids components, i.e. chrysosplenol D, chrysoplenetin, and artemetin and their glucuronidated metabolites in rats after oral administrations of A. annua extracts at a therapeutic ultra-low dose. The concentration of the intact form was determined directly, and the concentration of the glucuronidated form was assayed in the form of flavonoids aglycones, after treatment with ß-glucuronidase/sulfatase. The method was linear in the range of 0.5-300.0 ng/mL for chrysoplenetin and artemetin, and 2-600 ng/mL for chrysosplenol D. All the validation data conformed to the acceptance requirements. The study revealed a significantly higher exposure of the flavonoid constituents in conjugated forms in rats, with only trace intact from. Multiple oral doses of A. annua extracts led to a decreased plasma concentration levels for three flavonoids.
Assuntos
Antimaláricos/sangue , Artemisia annua/química , Flavonoides/sangue , Glucuronídeos/sangue , Extratos Vegetais/sangue , Administração Oral , Animais , Antimaláricos/administração & dosagem , Antimaláricos/farmacocinética , Cromatografia Líquida de Alta Pressão , Flavonoides/administração & dosagem , Flavonoides/farmacocinética , Glucuronídeos/administração & dosagem , Glucuronídeos/farmacocinética , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacocinética , Ratos , Ratos Wistar , Espectrometria de Massas em TandemRESUMO
Curcumin is a major component of the spice turmeric ( Curcuma longa), often used in food or as a dietary supplement. Many preclinical studies on curcumin suggest health benefits in many diseases due to its antioxidant/anti-inflammatory and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the acute pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received a 4 g dose of curcumin capsules with a standard breakfast. Plasma samples were collected at specified time points and analyzed for curcumin and its glucuronide levels. RNA was extracted from leukocytes and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were below the detection limit by HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and some levels of metabolite are in line with previous studies. PD marker antioxidant genes NRF2, HO-1, and NQO1 and epigenetic genes HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. COG PK is well-described by a one-compartment model, and the PK/PD of COG and its effect on antioxidant and epigenetic gene expression are captured by an indirect response model (IDR). A structural population PK model was sequentially established using a nonlinear mixed-effect model program (Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with the observed data. Taken together, these results show that the bioavailability of the parent curcumin compound is low, and oral administration of curcumin can still deliver detectable levels of curcumin glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic effects which could contribute to the overall health beneficial effects of curcumin.
Assuntos
Antioxidantes/farmacocinética , Curcumina/análogos & derivados , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucuronídeos/farmacocinética , Modelos Biológicos , Extratos Vegetais/farmacocinética , Administração Oral , Adolescente , Adulto , Antioxidantes/administração & dosagem , Disponibilidade Biológica , Cápsulas/administração & dosagem , Cápsulas/química , Curcuma , Curcumina/administração & dosagem , Curcumina/farmacocinética , Feminino , Glucuronídeos/administração & dosagem , Glucuronídeos/sangue , Voluntários Saudáveis , Heme Oxigenase-1/genética , Histona Desacetilases/genética , Humanos , Masculino , NAD(P)H Desidrogenase (Quinona)/genética , Fator 2 Relacionado a NF-E2/genética , Extratos Vegetais/administração & dosagem , Extratos Vegetais/sangue , Adulto JovemRESUMO
Cyclocarya paliurus has been used commonly to treat diabetes in China. However, the effective components and the effect of plant origin remain unclear. In this study, C. paliurus leaves with different chemical compositions were selected from five geographical locations, and their effects on streptozotocin (STZ)-induced diabetic mice were evaluated with both ethanol and aqueous extracts. Glucose levels, lipid levels, and biomarkers of liver and kidney function were measured. The principal components of both C. paliurus ethanol and aqueous extracts from different geographical locations differed quantitatively and qualitatively. Results showed that C. paliurus extracts with better antihyperglycemic effects were characterized by higher contents of total flavonoids, especially quercetin-3-O-glucuronide and kaempferol-3-O-glucuronide. Furthermore, significantly negative correlations were found between triterpenoids contents and lipid levels. These results revealed the potential antihyperglycemic capacity of C. paliurus flavonoids and the antihyperlipidemic effect of C. paliurus triterpenoids. Thus, we suggest that the composition of C. paliurus compounds might help to design therapeutic alternatives for the treatment of diabetes mellitus. However, geographic origins and the extraction solvents can also affect the effectiveness of the treatment as these factors influence the chemical compositions and thereby the biological activities.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Flavonoides/química , Hipolipemiantes/química , Juglandaceae/química , Triterpenos/química , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Flavonoides/administração & dosagem , Flavonoides/farmacologia , Glucuronídeos/administração & dosagem , Glucuronídeos/farmacologia , Hipolipemiantes/administração & dosagem , Hipolipemiantes/farmacologia , Quempferóis/administração & dosagem , Quempferóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Extratos Vegetais/química , Folhas de Planta/química , Quercetina/administração & dosagem , Quercetina/análogos & derivados , Quercetina/farmacologia , Estreptozocina , Triterpenos/administração & dosagem , Triterpenos/farmacologiaRESUMO
Our previous study demonstrated that quercetin-metabolite-enriched plasma (QP) but not quercetin itself upregulates peroxisome proliferator-activated receptor gamma (PPAR-γ) expression to induce G2/M arrest in A549 cells. In the present study, we incubated A549 cells with QP as well as quercetin-3-glucuronide (Q3G) and quercetin-3'-sulfate (Q3'S), two major metabolites of quercetin, to investigate the effects of quercetin metabolites on cell invasion and migration, the possible mechanisms and the role of PPAR-γ. We also compared the effects of QP with those of quercetin and troglitazone (TGZ), a PPAR-γ ligand. The results showed that QP significantly suppressed cell invasion and migration, as well as matrix metalloproteinases (MMPs)-2 activity and expression in a dose-dependent manner. The effects of 10% QP on those parameters were similar to those of 10µM quercetin and 20µM TGZ. However, QP and TGZ rather than quercetin itself increased the expressions of nm23-H1 and tissue inhibitor of metalloproteinase (TIMP-2). Furthermore, we demonstrated that Q3G and Q3'S also inhibited the protein expression of MMP-2. GW9662, a PPAR-γ antagonist, significantly diminished such an effect of Q3G and Q3'S. Silencing PPAR-γ expression in A549 cells also significantly diminished the suppression effect of Q3G and Q3'S on MMP-2 expression. Taken together, our study demonstrated that QP inhibited cell invasion and migration through nm23-H1/TIMP-2/MMP-2 associated mechanisms. The upregulation of PPAR-γ by quercetin metabolites such as Q3G and Q3'S could play an important role in the effects of QP.
Assuntos
Anticarcinógenos/metabolismo , Glucuronídeos/metabolismo , Neoplasias Pulmonares/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Proteínas de Neoplasias/metabolismo , PPAR gama/agonistas , Quercetina/análogos & derivados , Células A549 , Anilidas/farmacologia , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/farmacologia , Movimento Celular/efeitos dos fármacos , Cromanos/farmacologia , Suplementos Nutricionais , Repressão Enzimática/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Gerbillinae , Glucuronídeos/administração & dosagem , Glucuronídeos/sangue , Humanos , Ligantes , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Masculino , Metaloproteinase 2 da Matriz/química , Metaloproteinase 2 da Matriz/genética , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , PPAR gama/antagonistas & inibidores , PPAR gama/genética , PPAR gama/metabolismo , Quercetina/administração & dosagem , Quercetina/sangue , Quercetina/metabolismo , Interferência de RNA , Tiazolidinedionas/farmacologia , Troglitazona , Regulação para Cima/efeitos dos fármacosRESUMO
Scutellariae Radix (SR) has been extensively prescribed in folk medicines due to its notable beneficial activities. The flavonoid glucuronides baicalin (BG), wogonoside (WG), oroxylin A 7-O-ß-d-glucuronide (OG) and their aglycones baicalein, wogonin and oroxylin A, are the main components of the herb. So far, majority of previous studies failed to report the pharmacokinetics and none offered an explanation for the systemic exposures of these six flavonoids when the herbal extract was orally administered. In this study, when a SR extract was orally dosed to rats (800mg/kg, equivalent to BG 324.80, WG 124.00, OG 43.04, baicalein 25.36, wogonin 24.40, and oroxylin A 5.79mg/kg), all six flavonoids were detectable throughout the experimental period (48h) using an LC-MS/MS method with the Cmax and AUC0-48h of the glucuronides 10-130 times that of respective aglycones. As the lowest among the three glucuronides in the herb, OG was the most abundant in vivo, while the systemic exposure of wogonin was the highest amongst the three aglycones. The dose-normalized AUC0-48h descended in orders of OG/oroxylin A, WG/wogonin and BG/baicalein. Two di-conjugates of baicalein (BG glucuronide and BG glucoside), two BG isomers (minor BM1 and major BM2), and one WG isomer (wogonin 5-O-glucuronide) were detected in rat plasma. Semi-quantitation of the isomers with peak area data revealed that the AUPs (area under peak area ratio-time curves) of BG isomers were â¼3 times that of BG, yet the AUP of wogonin 5-O-glucuronide was only one seventh of WG. BM2, tentatively assigned as baicalein 6-O-glucuronide, was formed from both microbial isomerization of BG and hepatic glucuronidation of baicalein. Wogonin 5-O-glucuronide was only formed in hepatic glucuronidation of wogonin. Demethylated wogonin was observed in gut bacteria, offering an optional origin of BM1 apart from baicalein glucuronidation. Microbial isomerization of BG and extensive hepatic glucuronidation of baicalein to form BM2as well as a poorer intestinal permeability of baicalein (Papp×10(-6)cm/s) should account for the lower systemic exposures of BG and baicalein. Faster microbial hydrolysis of WG, high intestinal permeability (Papp×10(-5)cm/s) and less hepatic glucuronidation of wogonin explain the relatively high systemic exposure of wogonin. Sole microbial deglycosylation of OG, high intestinal permeability (Papp×10(-5)cm/s) and extensive hepatic glucuronidation of oroxylin A supported the highest systemic exposure of OG. Taken together, the oral kinetics of six flavonoid glucuronides and aglycones in the SR extract were simultaneously obtained. Microbial conversion, intestinal epithelial permeability and hepatic glucuronidation are determinant factors for their systemic exposures.
Assuntos
Flavanonas/farmacocinética , Flavonas/farmacocinética , Flavonoides/farmacocinética , Glucosídeos/farmacocinética , Glucuronídeos/farmacocinética , Extratos Vegetais/administração & dosagem , Administração Oral , Animais , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Flavanonas/administração & dosagem , Flavonas/administração & dosagem , Flavonoides/administração & dosagem , Glucosídeos/administração & dosagem , Glucuronídeos/administração & dosagem , Humanos , Masculino , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Scutellaria baicalensis , Espectrometria de Massas em TandemRESUMO
Epidemiology supports the important role of nutrition in prostate cancer (PCa) prevention. Pomegranate juice (PJ) exerts protective effects against PCa, mainly attributed to PJ ellagitannins (ETs). Our aim was to assess whether ETs or their metabolites ellagic acid and urolithins reach the human prostate upon consumption of ET-rich foods and to evaluate the effect on the expression of three proliferation biomarkers. Sixty-three patients with BPH or PCa were divided into controls and consumers of walnuts (35 g walnuts/day) or pomegranate (200 mL PJ/day) for 3 days before surgery. Independently of the ETs source, the main metabolite detected was urolithin A glucuronide, (3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one glucuronide) (up to 2 ng/g) together with the traces of urolithin B glucuronide, (3-hydroxy-6H-dibenzo[b,d]pyran-6-one glucuronide) and dimethyl ellagic acid. The small number of prostates containing metabolites was likely caused by clearance of the compounds during the fasting. This was corroborated in a parallel rat study and thus the presence of higher quantities of metabolites at earlier time points cannot be discarded. No apparent changes in the expression of CDKN1A, MKi-67 or c-Myc were found after consumption of the walnuts or PJ. Our results suggest that urolithin glucuronides and dimethyl ellagic acid may be the molecules responsible for the beneficial effects of PJ against PCa.
Assuntos
Cumarínicos/metabolismo , Ácido Elágico/metabolismo , Frutas , Glucuronídeos/metabolismo , Juglans , Lythraceae , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Idoso , Animais , Bebidas/análise , Biomarcadores Tumorais/metabolismo , Cumarínicos/administração & dosagem , Cumarínicos/química , Cumarínicos/urina , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Ácido Elágico/química , Ácido Elágico/urina , Frutas/química , Regulação Neoplásica da Expressão Gênica , Glucuronídeos/administração & dosagem , Glucuronídeos/química , Glucuronídeos/urina , Humanos , Taninos Hidrolisáveis/administração & dosagem , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/metabolismo , Intestinos/microbiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Juglans/química , Lythraceae/química , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/cirurgia , Hiperplasia Prostática/urina , Neoplasias da Próstata/prevenção & controle , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/urina , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Achyranthoside H methyl ester (AH-Me) is an oleanolic acid saponin derivative isolated from the roots of Achyranthes fauriei through diazomethane treatment. AH-Me exhibited significant cytotoxicity against human breast cancer MCF-7 and MDA-MB-453 cells, with respective ID(50) values of 4.0 and 6.5 muM: in the MTT assay. AH-Me is a unique saponin containing three methoxycarbonyl groups in the sugar moiety linked to the C-3 position of oleanolic acid. The demethylation of these methoxycarbonyl groups by alkaline hydrolysis caused a marked reduction of the cytotoxicity of AH-Me, suggesting that the methoxycarbonyl groups of AH-Me are key groups for the acquisition of cytotoxicity against human cancer cells. The staining of cancer cells with 4',6'-diamidino-2-phenylindole (DAPI) showed that the population of cells with altered nuclear morphology, for example chromatin condensation and fragmentation, increased markedly after AH-Me treatment. Exposure of MCF-7 and MDA-MB-453 cells to AH-Me resulted in a dose-dependent and time-dependent increase in the sub-G1 population, and in the cleavage of poly-ADP-ribose polymerase (PARP) followed by the formation of an 89 kD peptide. Pretreatment of the cells with the pan-caspase inhibitor z-VAD-fmk abolished the cleavage of PARP by AH-Me treatment and suppressed the antiproliferative effect of AH-Me on tumor cell growth. These results together led to the suggestion that AH-Me induces apoptosis via the caspase activation pathway in human breast cancer cells, and apoptosis is the major mode of the cytotoxic effect triggered by AH-Me.
Assuntos
Achyranthes/química , Neoplasias da Mama/tratamento farmacológico , Caspases/efeitos dos fármacos , Glucuronídeos/administração & dosagem , Saponinas/administração & dosagem , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática , Feminino , Glucuronídeos/química , Glucuronídeos/isolamento & purificação , Humanos , Hidrólise , Concentração Inibidora 50 , Raízes de Plantas , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Saponinas/química , Saponinas/isolamento & purificação , Fatores de TempoRESUMO
19-Nor-4-androstenediol (NOL) is a prohormone of nandrolone (ND). Both substances are included in the WADA List of Prohibited Classes of Substances and their administration is determined by the presence of 19-norandrosterone (NA) with the urinary threshold concentration of 2 ng mL(-1). Routine analytical procedures allow the determination of NA excreted free and conjugated with glucuronic acid, but amounts of ND and NOL metabolites are also excreted in the sulphate fraction. The aim of this study is to determine the urinary metabolic profile after oral administration of a nutritional supplement containing NOL. Urine samples were collected up to 96 h following supplement administration and were extracted to obtain separately three metabolic fractions: free, glucuronide and sulphate. Extraction with tert-butyl methyl ether was performed after the hydrolysis steps and trimethylsilyl derivatives were analyzed by gas chromatography/mass spectrometry (GC/MS). After oral administration of NOL, the main metabolites detected were NA and noretiocholanolone (NE) in the glucuronide and sulphate fractions. The relative abundances of each metabolite in each fraction fluctuate with time; a few hours after administration the main metabolite was NA glucuronide whereas in the last sample (4 days after administration) the main metabolite was the NA sulphate and the second was the NE glucuronide. During the studied period almost half of the dose was excreted and the main metabolites were still found in urine after 96 h. Norepiandrosterone and norepietiocholanolone were also detected only in the sulphate fraction. Our results suggest that sulphate metabolites should be taken into consideration in order to increase the retrospectivity in the detection of 19-norsteroids after oral administration.
Assuntos
Dopagem Esportivo/prevenção & controle , Cromatografia Gasosa-Espectrometria de Massas/métodos , Glucuronídeos/urina , Nandrolona/urina , Detecção do Abuso de Substâncias/métodos , Sulfatos/urina , Urinálise/métodos , Administração Oral , Adulto , Glucuronídeos/administração & dosagem , Humanos , Masculino , Nandrolona/administração & dosagem , Sulfatos/administração & dosagemRESUMO
A new flavonoid glucuronide, apigenin 7-O-beta-D-(4'-caffeoyl)glucuronide (1), and the known compound, apigenin 7-O-beta-D-glucurnoide, were isolated from the flowers of Chrysanthemum morifolium, along with five known flavonoids. The structure of 1 was elucidated by the aid of spectroscopic analyses. Among isolated compounds, apigenin 7-O-beta-D-(4"-caffeoyl)glucuronide showed strong HIV-1 integrase inhibitory activity (IC (50) = 7.2 +/- 3.4 microg/ml) and anti-HIV activity in a cell culture assay (EC (50) = 41.86 +/- 1.43 microg/ml) using HIV-I (IIIB) infected MT-4 cells.