- Extracellular melanogenesis inhibitory activity and the structure-activity relationships of ugonins from Helminthostachys zeylanica roots
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Ugonin J, K, and L, which are luteolin derivatives, were isolated from Helminthostachys zeylanica roots by a series of chromatographic separations of a 50% ethanol/water extract. They were identified using nuclear magnetic resonance (NMR), ultraviolet (UV) spectra, and ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF-MS). In this study, the intra and extracellular melanogenic activity of the ugonins were determined using B16 melanoma cells. The results showed that ugonin J at 12.5, 25, and 50 μM reduced extracellular melanin contents to 75, 16, and 14%, respectively, compared to the control. This indicates that ugonin J showed a stronger activity than arbutin, used as the positive control. Moreover, ugonin K showed a more potent inhibition with 19, 8, and 9% extracellular melanin reduction at the same concentrations, than that shown by ugonin J. In contrast, ugonin L did not inhibit intra- or extracellular melanogenic activity. Furthermore, in order to investigate the structure-activity relationships of the ugonins, the intra- and extracellular melanogenic activity of luteolin, methylluteolin, quercetin, eriodictyol, apigenin, and chrysin were determined. Consequently, it was suggested that the catechol and flavone skeleton of ugonin K is essential for the extracellular melanogenic inhibitory activity, and the low polarity substituent groups on the A ring of ugonin K may increase the activity.
- Yamauchi, Kosei,Mitsunaga, Tohru,Itakura, Yuki,Batubara, Irmanida
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- Anti‐melanogenic properties of velutin and its analogs?
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Velutin, one of the flavones contained in natural plants, has various beneficial activities, such as skin whitening, as well as anti‐inflammatory, anti‐allergic, antioxidant, and antimicrobial activities. However, the relationship between the structure of velutin and its anti‐melanogenesis activity is not yet investigated. In this study, we obtained 12 velutin derivatives substituted at C5, C7, C3′, and C4′ of the flavone backbone with hydrogen, hydroxyl, and methoxy functionalities by chemical synthesis, to perform SAR analysis of velutin structural analogues. The SAR study revealed that the substitution of functional groups at C5, C7, C3′, and C4′ of the flavone backbone affects biological activities related to melanin synthesis. The coexistence of hydroxyl and methoxy at the C5 and C7 position is essential for inhibiting tyrosinase activity. However, 1,2‐diol compounds substituted at C3′ and C4′ of flavone backbone induce apoptosis of melanoma cells. Further, substitution at C3′ and C4′ with methoxy or hydrogen is essential for inhibiting melanogenesis. Thus, this study would be helpful for the development of natural‐derived functional materials to regulate melanin synthesis.
- Choe, Jung-Won,Heo, Hee-Young,Jung, Se-Hui,Kim, Jaehyun,Lee, Kooyeon
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- Sterubin: Enantioresolution and Configurational Stability, Enantiomeric Purity in Nature, and Neuroprotective Activity in Vitro and in Vivo
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Alzheimer′s disease (AD) is a neurological disorder with still no preventive or curative treatment. Flavonoids are phytochemicals with potential therapeutic value. Previous studies described the flavanone sterubin isolated from the Californian plant Eriodictyon californicum as a potent neuroprotectant in several in vitro assays. Herein, the resolution of synthetic racemic sterubin (1) into its two enantiomers, (R)-1 and (S)-1, is described, which has been performed on a chiral chromatographic phase, and their stereochemical assignment online by HPLC-ECD coupling. (R)-1 and (S)-1 showed comparable neuroprotection in vitro with no significant differences. While the pure stereoisomers were configurationally stable in methanol, fast racemization was observed in the presence of culture medium. We also established the occurrence of extracted sterubin as its pure (S)-enantiomer. Moreover, the activity of sterubin (1) was investigated for the first time in vivo, in an AD mouse model. Sterubin (1) showed a significant positive impact on short- and long-term memory at low dosages.
- Hofmann, Julian,Fayez, Shaimaa,Scheiner, Matthias,Hoffmann, Matthias,Oerter, Sabrina,Appelt-Menzel, Antje,Maher, Pamela,Maurice, Tangui,Bringmann, Gerhard,Decker, Michael
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p. 7299 - 7308
(2020/05/18)
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- Selective synthesis of 7-O-substituted luteolin derivatives and their melanonenesis and proliferation inhibitory activity in B16 melanoma cells
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In our previous study, the isolation of ugonin J, K, and L, which are luteolin derivatives, from the roots of Helminthostachys zeylanica and their identification as potent melanogenesis inhibitors, was described. The structure activity relationship (SAR) investigation in that study revealed that the catechol moiety in the B-ring of the flavone skeleton of ugonin K was important for its melanogenesis inhibitory activity, and the presence of the low polarity substituents at the C-7 position enhanced this activity. In order to further investigate the SAR of the C-7-substituent in the luteolin derivatives, different groups were selectively introduced at the C-7 position of luteolin after borax protection of the catechol hydroxyl group and the C-5 hydroxyl group. NMR and MS analysis of the borax protected derivatives revealed that the borax protects not only hydroxyl groups of catechol on the B ring but also the 5-hydroxyl group on the A ring. Eight luteolin derivatives were synthesized and evaluated for melanogenesis inhibitory effect in B16 melanoma cells. Two bulky groups and six alkoxyl groups were introduced at the C-7 position. The resulting luteolin derivatives showed improved melanogenesis and cell proliferation inhibitory activities. From among these derivatives, 7-O-hexylluteolin (7) showed the highest activity and inhibited the melanogenesis to 14% at 6.25 μM. The present study also revealed that the length of the carbon chain rather than the bulky substituent was more important for the melanogenesis inhibitory activity.
- Yamauchi, Kosei,Fujieda, Akari,Mitsunaga, Tohru
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supporting information
p. 2518 - 2522
(2018/06/20)
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- Modifications of the 7-hydroxyl group of the transthyretin ligand luteolin provide mechanistic insights into its binding properties and high plasma specificity
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Amyloid formation of the plasma protein transthyretin (TTR) has been linked to familial amyloid polyneuropathy and senile systemic amyloidosis. Binding of ligands within its natural hormone binding site can stabilize the tetrameric structure and impair amyloid formation. We have recently shown that the flavonoid luteolin stabilizes TTR in human plasma with a very high selectivity. Luteolin, however, is inactivated in vivo via glucuronidation for which the preferred site is the hydroxy group at position 7 on its aromatic A-ring. We have evaluated the properties of two luteolin variants in which the 7-hydroxy group has been exchanged for a chlorine (7-Cl-Lut) or a methoxy group (7-MeO-Lut). Using an in vitro model, based on human liver microsomes, we verified that these modifications increase the persistence of the drug. Crystal structure determinations show that 7-Cl-Lut binds similarly to luteolin. The larger MeO substituent cannot be accommodated within the same space as the chlorine or hydroxy group and as a result 7-MeO-Lut binds in the opposite direction with the methoxy group in position 7 facing the solvent. Both 7-Cl-Lut and 7-MeO-Lut qualify as high-affinity binders, but in contrast to luteolin, they display a highly non-specific binding to other plasma components. The binding of the two conformations and the key-interactions to TTR are discussed in detail. Taken together, these results show a proof-of-concept that the persistence of luteolin towards enzymatic modification can be increased. We reveal two alternative high-affinity binding modes of luteolin to TTR and that modification in position 7 is restricted only to small substituents if the original orientation of luteolin should be preserved. In addition, the present work provides a general and convenient method to evaluate the efficacy of TTR-stabilizing drugs under conditions similar to an in vivo environment.
- Nilsson, Lina,Larsson, Andreas,Begum, Afshan,Iakovleva, Irina,Carlsson, Marcus,Br?nnstr?m, Kristoffer,Sauer-Eriksson, A. Elisabeth,Olofsson, Anders
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- Synthesis of 3-Acyl- and 3-Carbamoylflavones
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Routes to 3-acyl-, 3-carboxamido- and polyhydroxylated flavones have been devised by application of isoxazole methodology and Heck-Stille couplings.Reductive ring opening of 3-alkoxyisoxazoles gives β-keto carboxamides in contrast with 3-alkoxy-2-isoxazolines, which give β-hydroxy esters.
- Ellemose, Steen,Kure, Niels,Torsell, Kurt B. G.
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p. 524 - 529
(2007/10/02)
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- On a Thermal Transmethylation Reaction with Flavon-5-methylethers
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Upon heating to 300 deg C partial luteolinemethylethers undergo transmethylation.A reaction mechanism is put foreward. - Key words: Flavonemethylethers, Thermal Transmethylation, TLC, HPLC, Reaction Mechanism
- Geiger, Hans,Casteele, Karel Vande,Sumere, Christiaan F. Van
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p. 393 - 396
(2007/10/02)
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