ABSTRACT
BACKGROUND: Protoapigenone (PA), a natural flavonoid possessing an unusual p-quinol moiety on its B ring, is a prospective novel lead compound against cancer currently in development, together with WYC0209, a potent synthetic PA analog. Structure activity relationships (SAR) concerning different 1'-O-alkyl side-chains were also studied on two sets of derivatives. MATERIALS AND METHODS: Fifteen 1'-O-alkyl protoflavone derivatives were synthesized from genkwanin or 4'-hydroxy-6-methylflavone, thirteen of which are new compounds. All compounds were tested for their cytotoxic effect on four human cancer cell lines, such as HepG2 and Hep3B (hepatic), A549 (lung) and MDA-MB-231 (breast) cell lines, with doxorubicin as a positive control. All compounds, as well as PA, WYC0209 and fourteen of their previously reported analogs were also tested on a multidrug-resistant (MDR) sub-cell line of L5178 mouse T-cell lymphoma and on its parental counterpart (PAR). RESULTS: In general, derivatives bearing a free hydroxyl group at C-1' exerted the strongest activities, while C-1'-substituted compounds were found to be much weaker. Derivatives of 6-methylflavone exhibited mild, but statistically significant selectivity towards the MDR cell line. CONCLUSION: The results are in agreement with our previous findings for fundamental SAR of protoflavones. 6-Methylated protoflavones may serve as valuable leads for developing selective compounds against MDR cancer. Identical activity of other derivatives on the PAR and MDR cell lines suggests that cancer cells cannot exhibit resistance to protoflavones by ABCB1 efflux pump overexpression.
Subject(s)
Antineoplastic Agents/pharmacology , Flavones/pharmacology , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Flavones/chemistry , Hep G2 Cells , Humans , Leukemia L5178/drug therapy , Mice , Structure-Activity RelationshipABSTRACT
Chronic hepatitis C virus (HCV) infection ultimately leads to chronic hepatitis, hepatic cirrhosis and hepatocellular carcinoma (HCC). As the standard treatment is not completely efficacious, a safer and more effective agent against HCV infection needs to be developed. In this report, we demonstrated that 3-hydroxy caruilignan C (3-HCL-C) isolated from Swietenia macrophylla stems exhibited high anti-HCV activity at both protein and RNA levels at nontoxic concentrations, with an EC(50) value of 10.5 ± 1.2 µm. Combinations of 3-HCL-C and interferon-α (IFN-α), an HCV NS5B polymerase inhibitor (2'-C-methylcytidine; NM-107) or an HCV NS3/4A protease inhibitor (Telaprevir; VX-950) increased the suppression of HCV RNA replication. The results suggested that 3-HCL-C may be a potential anti-viral agent. We then demonstrated that 3-HCL-C interfered with HCV replication by inducing IFN-stimulated response element transcription and IFN-dependent anti-viral gene expression.
Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/drug effects , Lignans/pharmacology , Meliaceae/chemistry , Plant Extracts/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Humans , Interferon-alpha/pharmacology , Lignans/chemistry , Lignans/isolation & purification , Microbial Sensitivity Tests , Oligopeptides/pharmacology , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Stems/chemistry , Virus Replication/drug effectsABSTRACT
Chronic hepatitis C virus (HCV) infection is associated with chronic inflammation of liver, which leads to the development of cirrhosis and hepatocellular carcinoma (HCC). Because of severe side effects and only a 50-70% cure rate in genotype 1 HCV-infected patients upon current standard treatment with pegylated interferon-α plus ribavirin, new therapeutic regimens are still needed. San-Huang-Xie-Xin-Tang (SHXT) is a transitional Chinese herbal formula, composed of Rhei rhizoma, Scutellaria radix and Coptidis rhizome, and possesses anti-inflammatory effect. Here, we describe a (+)-catechin-containing fraction extracted from SHXT, referred as SHXT-frC, exhibited effective inhibition of HCV replication, with selectivity index value (SI; CC50 /EC50) of 84, and displayed synergistic anti-HCV effects when combined with interferon-α, HCV protease inhibitor telaprevir or polymerase inhibitor 2'-C-methylcytidine. The activation of factor-κB (NF-κB) and cyclooxygenase-2 (COX-2) signalling pathway has particular relevance to HCV-associated HCC. SHXT-frC treatment also caused a concentration-dependent decrease in the induction of COX-2 and NF-κB expression caused by either HCV replication or HCV NS5A protein. Collectively, SHXT-frC could be an adjuvant treatment for patients with HCV-induced liver diseases.
Subject(s)
Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/biosynthesis , Drugs, Chinese Herbal/pharmacology , Hepacivirus/drug effects , Virus Replication/drug effects , Antiviral Agents/pharmacology , Catechin/pharmacology , Cell Line , Cyclooxygenase 2/genetics , Cytidine/analogs & derivatives , Cytidine/therapeutic use , Drug Therapy, Combination , Hepacivirus/physiology , Humans , Interferon-alpha/therapeutic use , NF-kappa B/biosynthesis , NF-kappa B/metabolism , Oligopeptides/therapeutic use , Signal Transduction/drug effects , Viral Nonstructural Proteins/metabolismABSTRACT
A new triterpenoid named melliferone (1), three known triterpenoids, moronic acid (2), anwuweizonic acid (3), and betulonic acid (4), and four known aromatic compounds (5-8) were isolated from Brazilian propolis and tested for anti-HIV activity in H9 lymphocytes. Moronic acid (2) showed significant anti-HIV activity (EC(50) <0.1 microg/mL, TI >186) and was modified to develop more potent anti-AIDS agents.
Subject(s)
Anti-HIV Agents/isolation & purification , Myrtaceae/chemistry , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Propolis/chemistry , Triterpenes/isolation & purification , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Brazil , Cells, Cultured/drug effects , Drug Evaluation, Preclinical , Enzyme-Linked Immunosorbent Assay , HIV-1/drug effects , Humans , Inhibitory Concentration 50 , Lymphocytes/drug effects , Lymphocytes/virology , Magnetic Resonance Spectroscopy , Molecular Structure , Plants, Medicinal/chemistry , Structure-Activity Relationship , Triterpenes/chemistry , Triterpenes/pharmacology , Zidovudine/pharmacologyABSTRACT
A novel type of alpha,beta-butenolide alkaloid, uncinine (1), two novel oxoaporphines, artabonatine C (2) and artabonatine D (3), a new oxazoloaporphine, artabonatine E (4), and a new 7,7'-bisdehydroaporphine, artabonatine F (5), along with 25 known alkaloids, were isolated from Artabotrys uncinatus. The structures of 1-5 were determined using NMR and mass spectral data. Atherospermidine and squamolone exhibited cytotoxicity against hepatocarcinoma cancer cell lines (Hep G(2) and 2,2,15), and the activity of some of the alkaloids in an antithrombin assay is also discussed.
Subject(s)
Alkaloids/isolation & purification , Annonaceae/chemistry , Porphyrins/isolation & purification , Alkaloids/chemistry , Alkaloids/pharmacology , Antithrombins/metabolism , Aporphines/pharmacology , Carcinoma, Hepatocellular , Chromatography, Thin Layer , Drug Screening Assays, Antitumor , Fibrinogen/pharmacology , Gas Chromatography-Mass Spectrometry , Heparin/pharmacology , Humans , Isoquinolines/pharmacology , Magnetic Resonance Spectroscopy , Medicine, Chinese Traditional , Molecular Conformation , Molecular Structure , Plant Leaves/chemistry , Plant Roots/chemistry , Plant Stems/chemistry , Plants, Medicinal/chemistry , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/isolation & purification , Platelet Aggregation Inhibitors/pharmacology , Porphyrins/chemistry , Porphyrins/pharmacology , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Taiwan , Thrombin/metabolism , Tumor Cells, Cultured/drug effectsABSTRACT
Bullatacin, isolated from the fruit of Annona atemoya, is one of the most potentially effective antitumor annonaceous acetogenins. Bullatacin was studied here for its ability to inhibit the proliferation of 2.2.15 cells, hepatitis B virus (HBV) DNA transfected human hepatocarcinoma cell line. It was found that bullatacin induced cytotoxicity of 2.2.15 cells in a time- and dose-dependent manner. Fifty percent effective dose (ED50) on day 1 of exposure to bullatacin were 7.8 +/- 2.5 nM for 2.2.15 cells. [3H]-Thymidine incorporation assays showed almost the same results. Bullatacin-treatment also reduced concentrations of hepatitis B surface antigen (HBsAg) in the cultured medium released from 2.2.15 cells, coincident with the decrease in the cell proliferation. Analysis of mophological changes of bullatacin-treated 2.2.15 by inverted phase-contrast microscope and eletron microscopy revealed a possible model of action for bullatacin to inhibit proliferation of 2.2.15 cells by inducing apoptosis. Most of the bullatacin-induced cell death was found to be due to apoptosis, as determined by double staining with fluorescein-isothiocyanate (FITC)-labeled annexin V and propidium iodide (PI).
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Carcinoma, Hepatocellular/pathology , Furans/pharmacology , Liver Neoplasms/pathology , Annexin A5/metabolism , Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Cell Death/drug effects , Cell Division/drug effects , Culture Media, Conditioned/metabolism , DNA/biosynthesis , DNA/drug effects , Dose-Response Relationship, Drug , Ficoll/analogs & derivatives , Ficoll/metabolism , Flow Cytometry , Fluorescein-5-isothiocyanate/analogs & derivatives , Fluorescein-5-isothiocyanate/metabolism , Furans/therapeutic use , Hepatitis B Surface Antigens/metabolism , Humans , Liver Neoplasms/drug therapy , Propidium/metabolism , Tumor Cells, Cultured/cytology , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/pathologyABSTRACT
Seven new annonaceous acetogenins, muricins A-G (1-7), as well as five known compounds, a mixture of muricatetrocin A (8) and muricatetrocin B (9), longifolicin (10), corossolin (11), and corossolone (12), were isolated from the seeds of Annona muricata. The structures of all isolates were elucidated and characterized by spectral and chemical methods. These acetogenins showed significantly selective in vitro cytotoxicities toward the human hepatoma cell lines Hep G(2) and 2,2,15.
Subject(s)
Antineoplastic Agents, Phytogenic/isolation & purification , Furans/isolation & purification , Plants, Medicinal/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Carcinoma, Hepatocellular/metabolism , Furans/chemistry , Furans/pharmacology , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Seeds/chemistry , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Taiwan , Tumor Cells, Cultured/drug effectsABSTRACT
A novel alkaloid, hydrachine A (3), has been isolated, along with 15 known compounds, from the roots of Hydrangea chinensis. The structure and stereochemistry of the new alkaloid 3 was determined using extensive 2D NMR data.
Subject(s)
Alkaloids/isolation & purification , Drugs, Chinese Herbal/chemistry , Plants, Medicinal/chemistry , Alkaloids/chemistry , Alkaloids/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , Plant Roots/chemistryABSTRACT
Bioassay-directed fractionation of the stems of Rollinia mucosa led to the isolation of new N-methoxycarbonyl aporphine alkaloids, romucosine A (1), romucosine B (2), romucosine C (3), and romucosine D (4), along with the known alkaloid, N-methoxylcarbonyl-nornuciferine (5). Alkaloids 1 and 4 exhibited significant inhibition of collagen, arachidonic acid, and platelet activating factor-induced platelet aggregation, and alkaloid 3 also showed an inhibitory effect on arachidonic acid induced platelet aggregation.
Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Aporphines/chemistry , Aporphines/pharmacology , Magnoliopsida/chemistry , Platelet Aggregation Inhibitors/pharmacology , Alkaloids/isolation & purification , Aporphines/isolation & purification , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Molecular Structure , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/isolation & purification , Spectrometry, Mass, Electrospray IonizationABSTRACT
A new guaipyridine sesquiterpene alkaloid, cananodine (1), and two new eudesmane sesquiterpenes, cryptomeridiol 11-alpha-L-rhamnoside (2) and gamma-eudesmol 11-alpha-L-rhamnoside (3), along with gamma-eudesmol (4), were isolated from the fruits of Cananga odorata. The structures of compounds 1-3 were established on the basis of NMR and MS methods. In addition, compounds 1-4 and four previously reported alkaloids, cleistopholine (5), N-trans-feruloyltyramine (6), (+)-ushinsunine-beta-N-oxide (7), and lyscamine (8), were evaluated for cytotoxicity against two human hepatocarcinoma cell lines.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Fruit/chemistry , Plants, Medicinal/chemistry , Acetylation , Alkaloids/isolation & purification , Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/isolation & purification , China , Drug Screening Assays, Antitumor , Hydrolysis , Magnetic Resonance Spectroscopy , Mass Spectrometry , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Spectrophotometry, UltravioletABSTRACT
Four alkaloids, annocherine A, annocherine B, cherianoine, and romucosine H, along with one known alkaloid, artabonatine B, were isolated from the MeOH extract of the stems of Annona cherimola. Their structures were identified on the basis of both analysis of their spectral data and from chemical evidence.
Subject(s)
Alkaloids/chemistry , Plant Extracts/chemistry , Plants, Medicinal/chemistry , Alkaloids/isolation & purification , Medicine, Traditional , Methanol , Models, Molecular , Molecular Conformation , Molecular Structure , TaiwanABSTRACT
A new halimane diterpene, 3beta,5beta, 16alpha-trihydroxyhalima-13(14)-en-15,16-olide (1), and a new oxoprotoberberine alkaloid, (-)-8-oxopolyalthiaine (2), along with 20 known compounds, were isolated from a methanolic extract of Polyalthia longifolia var. pendula. The structures of compounds 1 and 2 were established by spectroscopic analysis. Several of these compounds were evaluated for cytotoxicity toward a small panel of human cell lines.
Subject(s)
Alkaloids/isolation & purification , Antineoplastic Agents, Phytogenic/isolation & purification , Berberine Alkaloids , Diterpenes/isolation & purification , Plants, Medicinal/chemistry , Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Diterpenes/pharmacology , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Plant Extracts/chemistry , Plant Extracts/pharmacology , Spectrophotometry, Ultraviolet , Tumor Cells, CulturedABSTRACT
Investigation of extracts of Fissistigma balansae and Fissistigma oldhamii resulted in the isolation of 11 aristolactams-stigmalactam (1), piperolactam A (2), piperolactam C (3), aristolactam AII (4), aristolactam AIIIa (5), aristolactam BII (6), aristolactam BIII (7), aristolactam FII (8), goniothalactam (9), enterocarpam I (10), and velutinam (11)-as well as two dioxoaporphines, noraristolodione (12) and norcepharadione B (13). The new compound 1 was identified by spectral data interpretation. Compounds 1-13 were subjected to antiplatelet aggregation testing.
Subject(s)
Lactams/isolation & purification , Plant Stems/chemistry , Animals , Biological Assay , Blood Platelets/drug effects , Cell Aggregation/drug effects , China , Chromatography, Gel , Chromatography, Thin Layer , Gas Chromatography-Mass Spectrometry , Lactams/chemistry , Lactams/pharmacology , Magnetic Resonance Spectroscopy , Phenanthrenes/chemistry , Phenanthrenes/isolation & purification , Phenanthrenes/pharmacology , Plants/chemistry , Rabbits , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , TaiwanABSTRACT
Chemical examination of the underground parts of Tupistra chinensis led to the isolation of two new 5beta-spirostane type steroidal sapogenins, tupichigenin B (1) and C (2), together with two known steroidal sapogenins, ranmogenin A (3) and delta25(27)-pentrogenin (4). The structures of 1 and 2 were established as spirost-25(27)-ene-1beta,3beta,4beta,5beta,6b eta-pentaol and 1beta,2beta,3beta,4beta,5beta-pentahydroxyspi rost-25(27)-en-6-one, respectively, on the basis of detailed analysis of their physical and spectral data.
Subject(s)
Liliaceae/chemistry , Plants, Medicinal/chemistry , Sapogenins/chemistry , Spirostans/chemistry , China , Magnetic Resonance Spectroscopy , Plant Roots/chemistry , Sapogenins/isolation & purification , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, Ultraviolet , Spirostans/isolation & purificationABSTRACT
Three new kaurane diterpenoids, annoglabasin C (16alpha-acetoxy-ent-kauran-19-oic acid-17-methyl ester) (1), annoglabasin D (16alpha-acetoxy-ent-kauran-19-al-17-methyl ester) (2), and annoglabasin E (16alpha-hydro-19-ol-ent-kauran-17-oic acid) (3), and a new norkaurane diterpenoid, annoglabasin F (16alpha-acetoxy-19-nor-ent-kauran-4alpha-ol-17-methyl ester) (4), along with 13 known kaurane derivatives were isolated from the stems of Annona glabra. 16alpha-Methoxy-ent-kauran-19-oic acid (5) and 16alpha-hydro-ent-kauran-17,19-dimethyl ester (6) were obtained for the first time as natural products. The structures of compounds 1-6 were characterized by spectral analysis.
Subject(s)
Diterpenes/isolation & purification , Plants/chemistry , Diterpenes/chemistry , Molecular Structure , Spectrum AnalysisABSTRACT
Three new alkaloids, promucosine (1), romucosine F (2), and romucosine G (3), along with 28 known compounds, were isolated from the MeOH extract of stems of Annona purpurea. The structures of 1-3 were determined on the basis of spectral data and chemical evidence.
Subject(s)
Alkaloids/isolation & purification , Plants, Medicinal/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Chemical , Spectrophotometry, Infrared , Spectrophotometry, UltravioletABSTRACT
From the underground parts of Tupistra chinensis, a novel polyhydroxylated spirostanol sapogenin, tupichigenin A [(20S, 22R)-spirost-25(27)-ene-1beta,2beta,3beta,5beta- tetraol] (1), was isolated and determined structurally on the basis of spectroscopic methods. Also isolated was the known steroidal sapogenin (20S, 22R)-spirost-25(27)-ene-1beta,2beta,3beta,4beta, 5beta, 7alpha-hexaol-6-one (2).
Subject(s)
Liliaceae/chemistry , Sapogenins/isolation & purification , Sterols/isolation & purification , China , Magnetic Resonance Spectroscopy , Molecular Conformation , Sapogenins/chemistry , Spectrometry, Mass, Fast Atom Bombardment , Sterols/chemistryABSTRACT
Two new sesquiterpenes, leitneridanin A (1) and leitneridanin B (2), and seven known compounds, lirioresinol B, (-)-pinoresinal, (+)-lariciresinol, quassimarin (3), simalikalactone D (4), 1-methoxycanthinone (5), and 5-methoxycanthinone (6), were isolated from Leitneria floridana. Their structures were identified on the basis of spectral data. In vitro biological evaluation showed that 5 is a potent anti-HIV agent (EC(50) 0.26 g/mL; TI >39) and that 3-6 suppressed the growth of a panel of human tumor cell lines (KB, A-549, HCT-8, CAKI-1, MCF-7, and SK-MEL-2). Compounds 3 and 4 were significantly active, with ED(50) values in the range of 0.26-0.012 g/mL.
Subject(s)
Anti-HIV Agents/isolation & purification , Antineoplastic Agents, Phytogenic/isolation & purification , Rosales/chemistry , Sesquiterpenes/isolation & purification , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Drug Screening Assays, Antitumor , Humans , Microbial Sensitivity Tests , Molecular Structure , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Spectrum Analysis , Tumor Cells, CulturedABSTRACT
Chromatographic fractionation of a MeOH extract from the stems of Annona cherimola led to the isolation of a new non-adjacent, bis-THF ring acetogenin (one THF ring being at C-4 and the other at C-16), aromin-A (1) along with the known cytotoxic acetogenin squamocin (2). The structures of these isolates were established by means of mass spectrometry and spectroscopic techniques.
Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Furans/chemistry , Lactones/chemistry , Plants, Medicinal , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/toxicity , Cell Survival/drug effects , Chromatography, Thin Layer , Furans/isolation & purification , Furans/toxicity , Lactones/isolation & purification , Lactones/toxicity , Plant Stems , Tumor Cells, CulturedABSTRACT
Four new compounds, a mixture of 20,23-cis-2,4-trans-bullatalicinone (1) and 20,23-cis-2,4-cis-bullatalicinone (2), rollimusin (3), and rolliacocin (4), along with eight known acetogenins, were isolated from an ethyl acetate extract of the unripe fruits of Rollinia mucosa. The structures and stereochemistry of 1-4 were determined on the basis of spectral data and chemical evidence.