- In vitro biological evaluation and molecular docking studies of natural and semisynthetic flavones from Gardenia oudiepe (Rubiaceae) as tyrosinase inhibitors
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Hyperpigmentation disorders are difficult to treat without causing permanent depigmentation or irritation. The most effective hypopigmenting agents are tyrosinase inhibitors, however some of those currently used have shown serious side effects. As several classes of flavonoids have already demonstrated ability to inhibit tyrosinase, a library of natural polymethoxyflavones isolated (1–7) from the bud exudate of Gardenia oudiepe and semi-synthetic derivatives (8,9) were evaluated. IC50 of the most active compounds were in the micromolar range. The strongest inhibitors 1, 2 and 3 all shared a 3′,4′-dimethoxy-5′-hydroxy trisubstituted B ring. These SAR conclusions were confirmed by molecular docking studies. The mode of interaction with the enzyme was elucidated, and important interactions between the most active compounds and catalytic residues of tyrosinase were observed. All of these data provided a library of compounds as potential leaders for the design of new depigmenting agents and formulations.
- Santi,Bouzidi,Gorod,Puiatti,Michel,Grougnet,Ortega
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- Polymethoxyflavones from Gardenia oudiepe (Rubiaceae) induce cytoskeleton disruption-mediated apoptosis and sensitize BRAF-mutated melanoma cells to chemotherapy
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A series of 10 natural and semisynthetic flavonoids (1 to 10) were obtained from Gardenia oudiepe (Rubiaceae), an endemic plant from New Caledonia. Most of them were polymethoxylated flavones (PMFs) of rare occurrence. After a cell viability screening test, PMFs 2 and 3 showed significant cytotoxic activity against A2058 human melanoma cells (IC50 = 3.92 and 8.18 μM, respectively) and were selected for in-depth pharmacological assays. Both compounds inhibited cell migration and induced apoptosis and cell cycle arrest after 72h of treatment. Immunofluorescence assays indicated that these outcomes were possibly related to the induction of cytoskeleton disruption associated to actin and tubulin depolymerization. These data were confirmed by molecular docking studies, which showed a good interaction between PMFs 2 and 3 and tubulin, particularly at the colchicine binding site. As A2058 are considered as chemoresistant to conventional chemotherapy, compounds 2 and 3 (?IC50) were associated to clinically-used antimelanoma drugs (vemurafenib and dacarbazine) and combined therapies efficacy was assessed by the MTT assay. PMFs 2 restored the sensitivity of A2058 cells to dacarbazine treatment (IC50 = 49.38 μM vs. >100 μM). Taken together, these data suggest that PMFs from G. oudiepe could be potential leaders for the design of new antimelanoma drugs.
- Beaugeard, Laureen,Beserra de Alencar Filho, Edilson,Guedes da Silva Almeida, Jackson Roberto,Michel, Sylvie,Picot, Laurent,Gon?alves de Oliveira-Júnior, Raimundo,Grougnet, Rapha?l,Marcoult-Fréville, Nolwenn,Prunier, Grégoire,Quintans-Júnior, Lucindo José,Sim?es Mour?o, Eduard David
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- Correlation study on methoxylation pattern of flavonoids and their heme-targeted antiplasmodial activity
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A library of 33 polymethoxylated flavones (PMF) was evaluated for heme-binding affinity by biomimetic MS assay and in vitro antiplasmodial activity on two strains of P. falciparum. Stability of heme adducts was discussed using the dissociation voltage at 50% (DV50). No correlation was observed between the methoxylation pattern and the antiparasitic activity, either for the 3D7 chloroquine-sensitive or for the W2 chloroquine-resistant P. falciparum strains. However, in each PMF family an increased DV50 was observed for the derivatives methoxylated in position 5. Measurement of intra-erythrocytic hemozoin formation of selected derivatives was performed and hemozoin concentration was inversely correlated with heme-binding affinity. Kaempferol showed no influence on hemozoin formation, reinforcing the hypothesis that this compound may exert in vitro antiplasmodial activity mostly through other pathways. Pentamethoxyquercetin has simultaneously demonstrated a significant biological activity and a strong interaction with heme, suggesting that inhibition of hemozoin formation is totally or partially responsible for its antiparasitic effect.
- Boutefnouchet, Sabrina,Bouzidi, Chouaha,Cojean, Sandrine,Figadère, Bruno,Grougnet, Rapha?l,Maciuk, Alexandre,Michel, Sylvie,Ortiz, Sergio,Vásquez-Ocmín, Pedro G.
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- Antivascular and anti-parasite activities of natural and hemisynthetic flavonoids from New Caledonian Gardenia species (Rubiaceae)
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A series of 16 flavonoids were isolated and prepared from bud exudate of Gardenia urvillei and Gardenia oudiepe, endemic to New Caledonia. Most of them are rare polymethoxylated flavones. Some of these compounds showed noticeable activity against Leishmania (Leishmania) amazonensis, Plasmodium falciparum and Trypanosoma brucei gambiense, in addition to tubulin polymerization inhibition at low micromolar concentration. We also provide a full set of NMR data as some of the flavones were incompletely described.
- Mai, Linh H.,Chabot, Guy G.,Grellier, Philippe,Quentin, Lionel,Dumontet, Vincent,Poulain, Cyril,Espindola, Laila S.,Michel, Sylvie,Vo, Hue T.B.,Deguin, Brigitte,Grougnet, Rapha?l
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supporting information
p. 93 - 100
(2015/03/05)
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- Regioselective iodination of flavonoids by N-iodosuccinimide under neutral conditions
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Regioselective synthesis of C-6 and C-8 monoiodo flavonoids, which are important intermediates for the synthesis of flavonoid natural products and drug molecules, was achieved by iodination of suitably alkylated flavonoids with N-iodosuccinimide (NIS) in DMF. The iodination gives either a C-6 or C-8 iodo flavonoid in high yield, depending on the protection pattern of the C-5 and C-7 OH groups. The mild and neutral conditions render this novel protocol particularly useful for the regioselective iodination of acid-sensitive substrates.
- Lu, Kui,Chu, Jie,Wang, Haomeng,Fu, Xiaoli,Quan, Dewu,Ding, Hongxia,Yao, Qingwei,Yu, Peng
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supporting information
p. 6345 - 6348
(2013/11/06)
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- Other chemical constituents isolated from Solanum crinitum Lam. (Solanaceae)
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The phytochemical investigation of Solanum crinitum Lam led to the isolation from the fruit trichomes of four flavonoids, tiliroside (1), astragalin (2), kaempferol (3), biochanin A-7-O-β-D-apiofuranosyl- (1→5)-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (7), along with 4-hydroxybenzoic acid (12), and four cinnamic acid derivatives, cis-and trans-coumaric acids (10 and 11) and cis- and trans- ethyl coumarate (8 and 9). Three tri-glycosyl-steroidal alkaloids, solamargine (13), 20-epi-solamargine (14) and solasonine (16) were isolated from the methanolic extract of the green fruits. The derivatives 3,5,7,4′-tretra-O-methyl-kaempferol (4), 3,7,4′-tri- O-methyl-kaempferol (5), 3,7,4′-tri-O-methyl-5-O-acetyl- kaempferol (6), the peracetyl-episolamargine (15) and peracetyl-solasonine (17) were prepared. The structures were established through the analysis of their spectral data. The complete 1H and 13C NMR data assignments of the new peracetyl derivatives of the alkaloids were made.
- Cornelius, Marli T. F.,De Carvalho, Ma?rio G.,Da Silva, Tania M. S.,Alves, Cassia C. F.,Siston, Ana P. N.,Alves, Kelly Z.,Sant'Anna, Carlos M. R.,Neto, Mario B.,Eberlin, Marcos N.,Braz-Filho, Raimundo
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experimental part
p. 2211 - 2219
(2011/10/17)
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- Prenylflavonoids and prenyl/alkyl-phloroacetophenones: Synthesis and antitumour biological evaluation
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Several prenylflavonoids have been synthesised and tested against human tumour cell lines. The prenyl unit has been geranyl or a labdane diterpene. These labdane-flavonoids have been synthesised for the first time. The antitumour activity increase with the prenylation at C-8 position. Twenty-three C and O-prenylated acylphloroglucinols have been synthesised as well. In this case the C-alkylation products have resulted, in general, more active.
- Basabe,De Román,Marcos,Diez,Blanco,Bodero,Mollinedo,Sierra,Urones
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scheme or table
p. 4258 - 4269
(2010/10/01)
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- Total synthesis of kaempferol and methylated kaempferol derivatives
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Kaempferol (1), a natural product from various plants, was synthesized in which the longest linear sequence is only seven steps in overall yields of 47% from commercially available 1,3,5-trimethoxybenzene (10). The methylated kaempferols 2-5 were also prepared by use of this concise synthetic methodology. The key transformations in this synthesis involved the I2 oxidative-promoting-cyclization and DDO oxidative hydroxylation. Several strategies to achieve 1 are provided.
- Lee, Yean-Jang,Wu, Tsao-Dong
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p. 201 - 206
(2007/10/03)
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- Studies of the Selective O-Alkylation and Dealkylation of Flavonoids. 10. Selective Demethylation of 7-Hydroxy-3,5,8-trimethoxyflavones with Anhydrous Aluminum Halide in Acetonitrile or Ether
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Demethylation of five 7-hydroxy-3,5,8-trimethoxyflavones and their acetates with anhydrous aluminum halides in acetonitrile or ether was studied and the following results were found. (1) The demethylation was apparently influenced by both solvents and afforded 5,7-dihydroxy-3,8-dimethoxyflavones in acetonitrile and 3,7-dihydroxy-5,8-dimethoxyflavones in ether as main products. (2) The demethylation with 5percent w/v anhydrous aluminum bromide in acetonitrile procedeed quantitatively to give a mixture of corresponding 5- and 3-hydroxyflavones, but that of 7-hydroxy-3,4',5,8-tetramethoxyflavone and its acetate with 10percent anhydrous aluminum chloride in acetonitrile afforded 6-acetyl-5,7-dihydroxy-3,4,8-trimethoxyflavone as a byproduct along with the 5- and 3-hydroxyflavones. (3) The demethylation of the acetates proceeded more smoothly than that of hydroxyflavones and was superior to that of the flavones with a hydroxy group. (4) These demethylations are available for the syntheses of 3- or 5-hydroxyflavones with no substituent at 6-position.
- Horie, Tokunaru,Tsukayama, Masao,Kawamura, Yasuhiko,Seno, Masamichi
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p. 4702 - 4709
(2007/10/02)
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- AMORPHASTILBOL, AN ANTIMICROBIAL AGENT FROM AMORPHA NANA
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Key Word Index - Amorpha nana; Leguminosae; amorphastilbol; 3,5-dihydroxy-7,4'-dimethoxyflavone; antimicrobial agents; chemistry; bioactivity.Abstract - Bioassay-directed fractionation of Amorpha nana demonstrated that the anti Gram positive/antitubercular constituent is amorphastilbol.The chemical structure of amorphastilbol was confirmed by chemical transformation to known (Radula variabilis) dihydroamorphastilbol and its methyl ether.Inactive 3,5-dihydroxy-7,4'-dimethoxyflavone was detected in this plant for the first time and identified by interconversion with kaempferol.All compounds were evaluated in vitro for antimicrobial spectrum and potency.
- Mitscher, Lester A.,Gollapudi, Sitaraghav Rao,Drake, Steven,Oburn, David S.
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p. 1481 - 1484
(2007/10/02)
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- 3-Alkoxyflavone antiviral agents
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Antiviral compositions containing 3-alkoxyflavone compounds as their active ingredients are disclosed.
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