ABSTRACT
To search for possible anti-tumor promoters, ten flavonoid derivatives (1-10) synthesized from morin and quercetin were examined for their inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation by a short-term in vitro assay. Of these compounds, pentaallyl ethers (9, 10) showed significant inhibitory effects on EBV-EA activation induced by the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate. Further, quercetin pentaallyl ether (10) exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.
Subject(s)
Flavonoids/metabolism , Herpesvirus 4, Human/metabolism , Skin Neoplasms/etiology , Skin Neoplasms/prevention & control , Skin Neoplasms/virology , Animals , Carcinogens , Dose-Response Relationship, Drug , Female , Flavonoids/chemistry , Lymphocytes/metabolism , Mice , Mice, Inbred ICR , Models, Chemical , Papilloma/etiology , Papilloma/metabolism , Quercetin/chemistry , Quercetin/metabolism , Tetradecanoylphorbol Acetate , Time FactorsABSTRACT
Two new flavanones and one chalcone were isolated from the peel of Citrus kinokuni Hort. ex Tanaka and identified as (2S)-5,6,7,8,4'-pentamethoxyflavanone (1), (2S)-5,6,7,3',4'-pentamethoxyflavanone (2) and 2'-hydroxy-3,4,3',4',6'-pentamethoxychalcone (3). The structures of new compounds were elucidated by spectroscopic analysis.
Subject(s)
Chalcone/chemistry , Citrus/chemistry , Flavanones , Flavonoids/chemistry , Chalcone/analogs & derivatives , Chalcones , Flavonoids/isolation & purification , Indicators and Reagents , Magnetic Resonance Spectroscopy , Spectrophotometry, UltravioletABSTRACT
The polymethoxyflavonoid (PMF), nobiletin (NOB), specifically occurs in citrus fruits, and is currently believed to be a promising anti-inflammatory and antitumor promoting agent. In the present study, we investigated the in vitro absorption and metabolism of NOB and compared them with those of the polyhydroxyflavonoid (PHF), luteolin (LT). NOB preferentially accumulated in a differentiated Caco-2 cell monolayer, which is a model for small intestinal epithelial cells, while LT did not. Treatment of NOB with a rat liver S-9 mixture led to the formation of 3'-demethyl-NOB, while that of LT did not. We thus suggest that PMFs including NOB have properties distinct from those of general flavonoids for absorption and metabolism in vitro.
Subject(s)
Anticarcinogenic Agents/metabolism , Citrus/chemistry , Flavones , Flavonoids/metabolism , Animals , Caco-2 Cells , Flavonoids/chemistry , Flavonoids/pharmacokinetics , Humans , Intestinal Absorption , Intestinal Mucosa/metabolism , Liver/metabolism , Luteolin , Molecular Structure , RatsABSTRACT
Nobiletin and 3,5,6,7,8,3',4'-heptamethoxyflavone (HPT), isolated from the peel of Citrus plants, were examined for the anti-tumor-initiating activity on two-stage carcinogenesis of mouse skin tumors induced by a nitric oxide donor, (+/-)-(E)-methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexenamide, as an initiator and 12-O-tetradecanoylphorbol-13-acetate as a promoter. HPT exhibited the remarkable anti-tumor-initiating effect on mouse skin and it suggested the possibility of HPT being a chemopreventive agent against nitric oxide (NO) carcinogenesis.
Subject(s)
Citrus/chemistry , Flavones , Flavonoids/pharmacology , Skin Neoplasms/prevention & control , 9,10-Dimethyl-1,2-benzanthracene/administration & dosage , Animals , Anticarcinogenic Agents/pharmacology , Carcinogens/administration & dosage , Female , Mice , Nitro Compounds/administration & dosage , Papilloma/chemically induced , Papilloma/prevention & control , Plant Extracts/chemistry , Plant Extracts/pharmacology , Skin Neoplasms/chemically induced , Specific Pathogen-Free Organisms , Tetradecanoylphorbol Acetate/adverse effects , Time FactorsABSTRACT
To search for possible anti-tumor promoters, thirteen flavones (1-13) obtained from the peel of Citrus plants were examined for their inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation by a short-term in vitro assay. Of these flavones, 3,5,6,7,8,3',4'-heptamethoxyflavone (HPT) (13) exhibited significant inhibitory effects on the EBV-EA activation induced by the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA). Further, compound 13 exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.
Subject(s)
Antigens, Viral/metabolism , Flavonoids/pharmacology , Papilloma/metabolism , Plant Extracts/pharmacology , Skin Neoplasms/metabolism , Virus Activation/drug effects , Animals , Female , Flavonoids/chemistry , Flavonoids/isolation & purification , Mice , Mice, Inbred ICR , Papilloma/chemically induced , Papilloma/drug therapy , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Skin Neoplasms/chemically induced , Skin Neoplasms/drug therapy , Tetradecanoylphorbol Acetate , Time FactorsABSTRACT
Four new furanone-coumarins, clauslactones-N (4), -O (5), -P (6) and -Q (7) were isolated from the leaves and twigs of Clausena excavata BURM. f. (Rutaceae) collected in Indonesia and their structures were elucidated by spectroscopic analysis.
Subject(s)
4-Butyrolactone/analogs & derivatives , Coumarins/chemistry , Plant Extracts/chemistry , 4-Butyrolactone/chemistry , Magnetic Resonance Spectroscopy , Models, ChemicalABSTRACT
To search useful compounds in Citrus fruit for cancer chemoprevention, we carried out a primary screening of extracts of fruit peels and seeds from 78 species of the genus Citrus and those from two Fortunella and one Poncirus species, which were closely related to the genus Citrus. These Citrus extracts inhibited the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) as a useful screening method for anti-tumor promoters. Our results indicated that Citrus containing substances may be inhibit susceptibility factors involved in the events leading to the development of cancer.
Subject(s)
Anticarcinogenic Agents/pharmacology , Citrus/chemistry , Herpesvirus 4, Human/growth & development , Virus Activation/drug effects , Animals , Antigens, Viral/physiology , Antiviral Agents/pharmacology , Burkitt Lymphoma/drug therapy , Carcinogens , Chick Embryo , Drug Screening Assays, Antitumor , Herpesvirus 4, Human/drug effects , Humans , Plant Extracts/pharmacology , Seeds/chemistry , Tetradecanoylphorbol Acetate , Tumor Cells, CulturedABSTRACT
Fifteen acridone alkaloids were examined for their antiproliferative activity toward monolayers and suspension of several types of cancer and normal human cell lines. As a result, atalaphyllidine (9), 5-hydroxy-N-methylseverifoline (11), atalaphyllinine (12), and des-N-methylnoracronycine (13) showed potent antiproliferative activity against tumor cell lines, whereas they have weak cytotoxicity on normal human cell lines. The structure-activity relationship established from the results revealed that a secondary amine, hydroxyl groups at C-1 and C-5, and a prenyl group at C-2 played an important role for antiproliferative activities of the tetracyclic acridones.
Subject(s)
Acridines/pharmacology , Alkaloids/pharmacology , Antineoplastic Agents/pharmacology , Acridines/chemistry , Acridines/isolation & purification , Acridones , Alkaloids/chemistry , Alkaloids/isolation & purification , Animals , Antineoplastic Agents/isolation & purification , Cell Division/drug effects , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Mice , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Fifteen acridone alkaloids were examined for their activity of induction of human promyelocytic leukemia cell (HL-60) differentiation. HL-60 cells were differentiated into mature monocyte/macrophage by atalaphyllidine (9), atalaphyllinine (12), and des-N-methylnoracronycine (13). The activities of NBT reduction, nonspecific esterase, and phagocytosis, were induced by 2.5 microM of 9, 12, and 13. After a 4-day treatment, 9, 12, and 13 at 10 microM inhibited clonal proliferation of HL-60 cells by 28, 96, and 63%, respectively. The structure-activity relationship established from the results revealed that hydroxyl group at C-1 and prenyl group at C-2 had an important role.
Subject(s)
Acridines/pharmacology , Alkaloids/pharmacology , HL-60 Cells/drug effects , Cell Differentiation/drug effects , Dose-Response Relationship, Drug , Humans , Photochemotherapy , Structure-Activity RelationshipABSTRACT
Twenty-five acridone alkaloids from Citrus plants were examined for their inhibitory effects on Epstein-Barr virus activation by a short-term in vitro assay. 5-Hydroxynoracronycine (20) and acrimarine-F (25) showed remarkable inhibitory effects.
Subject(s)
Acridines/pharmacology , Alkaloids/pharmacology , Antiviral Agents/pharmacology , Citrus , Herpesvirus 4, Human/growth & development , Virus Activation/drug effects , Acridines/isolation & purification , Alkaloids/isolation & purification , Antiviral Agents/isolation & purification , Cell Line , Herpesvirus 4, Human/drug effects , Humans , Plant Roots , Structure-Activity RelationshipABSTRACT
The potent weakly acidic uncoupler SF 6847 was modified by methylation of its phenolic OH group, and the effect of the resulting derivative, with no acid-dissociable group, on oxidative phosphorylation in rat liver mitochondria was examined. The methylated SF 6847 did not induce uncoupling at up to 40 microM, while SF 6847 uncoupled oxidative phosphorylation completely at about 20 nM, indicating that the acid-dissociable group is essential for uncoupling. The O-methylated SF 6847 at 20 microM did, however, inhibit state 3 respiration of mitochondria, although it did not inhibit electron-flow through the respiratory chain, ATPase activated by weakly acidic uncouplers or Pi-ATP exchange. At the same concentration, it also inhibited ATP synthesis in submitochondrial particles. These features are different from those of known inhibitors of oxidative phosphorylation. Thus, O-methylated SF 6847 is a unique inhibitor of oxidative phosphorylation. The possible identity of the uncoupler binding protein is discussed on the basis of these results.
Subject(s)
Nitriles/pharmacology , Oxidative Phosphorylation/drug effects , Uncoupling Agents/pharmacology , Adenosine Triphosphate/metabolism , Animals , Methylation , Mitochondria, Liver/drug effects , Proton-Translocating ATPases/metabolism , RatsABSTRACT
Two cytotoxic antileukemic alkaloids, the new 1,11-dimethoxycanthin-6-one (3) and the known 11-hydroxycanthin-6-one (1), as well as the known canthin-6-one (2) were isolated from the stem of Brucea antidysenterica. The structures of 1-3 were determined from their spectral data and X-ray analysis of the o-bromobenzoate of 1.
Subject(s)
Alkaloids/isolation & purification , Antineoplastic Agents, Phytogenic/isolation & purification , Alkaloids/pharmacology , Animals , Leukemia, Experimental/drug therapy , Magnetic Resonance Spectroscopy , X-Ray DiffractionABSTRACT
We reported recently (Yoshikawa, K. and Terada, H. (1982) J. Am. Chem. Soc. 104, 7644-7646) that the potent uncoupler of oxidative phosphorylation SF-6847 [3,5-di-tert-butyl-4-hydroxybenzylidene)malononitrile) shows unique intramolecular restricted rotation of the malononitrile moiety. In this study, values for the activation energy Ea of the restricted rotation of SF-6847 derivatives with the same alkyl chain R in both ortho positions of the phenolic hydroxyl group were determined from the temperature-dependent change in the 1H-NMR signals of their aromatic protons. The Ea values of the neutral forms of these derivatives were found to be the same irrespective of R, but those of the anionic forms increased with increase in the alkyl chain length of R. It was found that the restricted rotation of the malononitrile moiety regulates its electron-withdrawing ability in such a way as to keep the acid dissociability of these derivatives similar, overcoming the effect of steric hindrance by R. The protonophoric activity of these derivatives, in a phospholipid bilayer membrane and their uncoupling activity in rat-liver mitochondria were both found to depend on Ea of their anionic forms. The stability of the uncoupler anions regulated by the restricted rotation of the malononitrile group in a nonpolar membrane environment was found to be important for exhibition of these activities. The hydrophobicity of the anionic forms of these derivatives was suggested also to be affected by the intramolecular rotation.