- Synthesis of 5-Hydroxy-3′,4′,7-trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2-Mediated Anticancer Drug Resistance
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3′,4′,7-Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C-5 and several kinds of capping moiety at the C-7 hydroxy group, on the same 3′,4′-dimethoxy-substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP-expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI50). Of the synthesized compounds, the reversal effect of 5-hydroxy-3′,4′,7-trimethoxyflavone (HTMF, RI50 7.2 nm) towards 7-ethyl-10-hydroxycamptothecin (SN-38) was stronger than that of TMF (RI50 18 nm). Fluoro-substituted 5-fluoro-3′,4′,7-trimethoxyflavone (FTMF, RI50 25 nm) and monoglycosylated 7-(β-glucosyloxy)-5-hydroxy-3′,4′-dimethoxyflavone (GOHDMF, 91 nm) also exhibited reversal effects, whereas the di- and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01–10 μm upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μm TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP-mediated efflux and suppression of BCRP expression of the three effective synthesized flavones.
- Tsunekawa, Ryuji,Katayama, Kazuhiro,Hanaya, Kengo,Higashibayashi, Shuhei,Sugimoto, Yoshikazu,Sugai, Takeshi
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- Synthesis and Antiproliferative Activity of Thioxoflavones Mannich Base Derivatives
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Two series of 12 novel thioxoflavones Mannich base derivatives 5a–f and 6a–f were synthesized via Mannich reaction of 4′,7-dimethoxy-5-hydroxyflavothione (3) or 3′,4′,7-trimethoxy-5-hydroxyflavothione (4) with appropriate aliphatic amines or alicyclic amines and formaldehyde. Thioxoflavones 3 and 4 were prepared from 4′,7-dimethoxy-5-hydroxyflavone (1) and 3′,4′,7-trimethoxy-5-hydroxyflavone (2) with Lawesson's reagent, respectively. Their antiproliferative activities in vitro were evaluated on a panel of three human cell lines (HeLa, HCC1954, and SK-OV-3) by CCK-8 assay. The results showed that most of the thioxoflavones and their Mannich base derivatives exhibited potential antiproliferative activities on the tested cancer cell lines, with IC50 values ranging from 9.16 to 55.50 μM. In particular, thioxoflavone 4 and the thioxoflavone Mannich base derivatives 5a and 5d showed the best antiproliferative activity on all three human cancer cell lines; they are promising candidates worthy of further development. The structures of all synthesized compounds were confirmed by 1H NMR, 13C NMR, IR, and MS techniques.
- Li, Wei,Li, Xueli,Liu, Manhui,Wang, Qiuan
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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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- Synthesis, in Silico and in vitro evaluation of some flavone derivatives for Acetylcholinesterase and BACE-1 inhibitory activity
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Acetylcholinesterase (AChE) and β-secretase (BACE-1) have become attractive therapeutic targets for Alzheimer’s disease (AD). Flavones are flavonoid derivatives with various bioactive effects, including AChE and BACE-1 inhibition. In the present work, a series of 14 flavone derivatives was synthesized in relatively high yields (35–85%). Six of the synthetic flavones (B4, B5, B6, B8, D6 and D7) had completely new structures. The AChE and BACE-1 inhibitory activities were tested, giving pIC50 3.47–4.59 (AChE) and 4.15–5.80 (BACE-1). Three compounds (B3, D5 and D6) exhibited the highest biological effects on both AChE and BACE-1. A molecular docking investigation was conducted to explain the experimental results. These molecules could be employed for further studies to discover new structures with dual action on both AChE and BACE-1 that could serve as novel therapies for AD.
- Le, Minh-Tri,Mai, Thanh-Tan,Nguyen, Ngoc-Le,Thai, Khac-Minh,Tran, Thai-Son,Tran, Thanh-Dao,Tran, The-Huan
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- Synthesis of Benzopyran-Fused Flavone Derivatives via Microwave-Assisted Intramolecular C-H Activation
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A microwave-assisted intramolecular direct arylation method for the synthesis of benzopyran-fused flavone derivatives containing natural flavone backbones is described. Different polyalkoxy flavones were synthesized and functionalized with 2-bromobenzyl bromide. The resulting compounds were subjected to palladium-catalyzed intramolecular direct arylation reactions supported by microwave irradiation to produce fused tetracyclic flavones. In the case of the 7-substituted chrysin derivative, the regioselectivity of the coupling was also examined.
- Sipos, Zoltán,Kónya, Krisztina
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p. 1610 - 1620
(2018/03/21)
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- Substituted flavonoid compound and its preparation and use
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The invention relates to the technical field of biological medicines, and firstly provides a flavonoid compound shown as a general formula (I) and an application of the flavonoid compound in preparation of an anti-tumor medicine. In addition, the invention further provides a medicine composition containing the flavonoid compound. The flavonoid compound can be competitively combined with Bcl-2, Bcl-xL and Mcl-1 protein so as to specifically cause the apoptosis of tumor cells, so that the flavonoid compound can be possibly developed into a safe and efficient anti-cancer medicine of targeted Bcl-2 family protein. In addition, the compound provided by the invention also has good antifungal activity. Thus, based on data, the compound provided by the invention has good development prospects.
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- Acidic rearrangement of benzyl group in flavone benzyl ethers and its regioselectivity
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Abstract The benzyl-substituted flavone compounds are rare in nature, while some of which have interesting biological activities. The total synthesis of benzyl-substituted flavone derivatives via the acidic rearrangement of benzyl groups in flavone benzyl ethers, and the complicated regioselectivity of the rearrangement were reported. The regioselectivity was proposed to be determined by the steric hindrance as well as the ease of electrophilic substitution reaction for benzyl cations at different positions of corresponding debenzylated flavone compounds.
- Wang, Chong-Qing,Chen, Xin,Jiang, Jun-Hang,Tang, Hui,Zhu, Kong-Kai,Zhou, You-Jun,Zheng, Can-Hui,Zhu, Ju
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supporting information
p. 793 - 796
(2015/08/03)
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- Synthesis and anticholinesterase inhibitory activity of mannich base derivatives of flavonoids
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Hesperidin-derived 2'-hydroxy-3,4,4',6'-tetramethoxy-chalcone and 5-hydroxy-7,3',4'-trimethoxy-flavone underwent reaction with formaldehyde and a series of secondary amines producing 11 new Mannich base derivatives of flavonoids. The aminomethylation occurred preferentially at the C-3' position of the chalcone and at the C-6 position of flavone. These aminated derivatives of flavonoids were evaluated as inhibitors of acetylcholinesterase (AChE) and the results showed that two of them exhibited excellent AChE inhibitory activity.
- Duan, Keke,Liu, Haoran,Fan, Haoqun,Zhang, Jing,Wang, Qiuan
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p. 443 - 446
(2014/08/05)
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- NMR of a series of novel hydroxyflavothiones
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Alkylated hydroxyflavothiones, namely flavothione, 5-hydroxyflavothione, 5,7-dihydroxyflavothione (chrysinthione), 7-dodecyloxy-5-hydroxyflavothione, 7-butyloxy-5-hydroxyflavothione, 2′,3,4′,7-tetramethoxy-5- hydroxyflavothione, 3,3′,4′,7-tetramethoxy-5-hydroxyflavothione, 7-butyloxy-4′,5-dihydroxyflavothione and 7-butyloxy-4′,5- hydroxyflavanonethione have been synthesized from the corresponding hydroxyflavones in two steps, alkylation of the non-hydrogen-bonded hydroxyl groups by bromoalkanes or dimethyl sulfate followedby conversion of the carbonyl group to a thione using Lawesson's Reagent undermicrowave irradiation and solvent-free conditions. Part of the alkylated flavanone, 7-butyloxy-4′,5- dihydroxyflavanone, was oxidized during the treatment with Lawesson's reagent to yield a second product 7-butyloxy-4′,5-dihydroxyflavothione in addition to the target product butyloxy-4′,5-hydroxyflavanonethione. Deuterium isotope effects on 13C chemical shifts have been measured in hydroxyflavones, isoflavones, flavanones and the thio analogs. Formal four-bond deuterium isotope effects on 13C chemical shifts, nΔC= S(OD) are very sensitive to variations in structures and substitution patterns. Density functional theory (DFT) calculations are carried out to obtain geometries. Correlations relating distances around the hydrogen bond system to the deuterium isotope effects on 13C chemical shifts are discussed. 13C chemical shifts are calculated by DFT methods. Effects of thiocarbonyl anisotropies are suggested.
- Nguyen, Tuyen Kim Pham,Nguyen, Kim Phi Phung,Kamounah, Fadhil S.,Zhang, Wei,Hansen, Poul Erik
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experimental part
p. 1043 - 1054
(2010/08/05)
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- Chromenone derivatives useful for the treatment of neurodegenerative diseases
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Compounds of general formula (I) and (II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 have the meanings given in the specification, are useful in the treatment of neurodegenerative disease.
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Page/Page column 16
(2009/11/30)
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- Regioselective hydroxylation of 2-hydroxychalcones by dimethyldioxirane towards polymethoxylated flavonoids
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The flavone nucleus is part of a large number of natural products and medicinal compounds. In this presentation the novel regioselective hydroxylation of hydroxyarenes with DMD is described. The results showed further that flavonoids with 5-hydroxy group were selectively oxyfunctionalized at the para-position C8 carbon atom by DMD. Finally, according to this methodology, the naturally occurring isosinensetin, tangeretin, sinensetin, nobiletin, natsudaidain, gardenin B, 3,3′,4′,5,6,7,8- heptamethoxyflavone, quercetin and its derivatives were synthesized.
- Chu, Han-Wei,Wu, Huan-Ting,Lee, Yean-Jang
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p. 2647 - 2655
(2007/10/03)
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- Structural requirements of flavonoids and related compounds for aldose reductase inhibitory activity
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The methanolic extracts of several natural medicines and medicinal foodstuffs were found to show an inhibitory effect on rat lens aldose reductase. In most cases, flavonoids were isolated as the active constituents by bioassay-guided separation, and among them, quercitrin (IC50=0.15 μM), guaijaverin (0.18 μM), and desmanthin-1 (0.082 μM) exhibited potent inhibitory activity. Desmanthin-1 showed the most potent activity, which was equivalent to that of a commercial synthetic aldose reductase inhibitor, epalrestat (0.072 μM). In order to clarify the structural requirements of flavonoids for aldose reductase inhibitory activity, various flavonoids and related compounds were examined. The results suggested the following structural requirements of flavonoid: 1) the flavones and flavonols having the 7-hydroxyl and/or catechol moiety at the B ring (the 3′,4′-dihydroxyl moiety) exhibit the strong activity; 2) the 5-hydroxyl moiety does not affect the activity; 3) the 3-hydroxyl and 7-O-glucosyl moieties reduce the activity; 4) the 2-3 double bond enhances the activity; 5) the flavones and flavonols having the catechol moiety at the B ring exhibit stronger activity than those having the pyrogallol moiety (the 3′,4′,5′-trihydroxyl moiety).
- Matsuda, Hisashi,Morikawa, Toshio,Toguchida, Iwao,Yoshikawa, Masayuki
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p. 788 - 795
(2007/10/03)
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- Kinetics and Mechanism of the Cyclisation of 2',6'-Dihydroxychalcone and Derivates
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pH-Rate profiles are reported for the cyclisation in water to 5-hydroxyflavanones of 2',6'-dihydroxychalcone (1) and its 4-methoxy (2), 3,4-dimethoxy (3), 3,4,5-trimethoxy (4), 2,4,6-trimethoxy (5), 4-chloro (6), and 3,4,4'-trimethoxy (8) derivates.As for the previously studied 2',6'-dihydroxy-4,4'-dimethoxychalcone (7), rate coefficients are established for acid-catalysed cyclisation of neutral chalcone, for unimolecular cyclisation of the neutral, monoanionic, and dianionic chalcone, and for the base-catalysed reverse ring-opening reaction.Cyclisation of the monoanion of 2',6'-dihydroxychalcone is almost 40 times faster than that of the monoanion of the 2'-hydroxy-6'-methoxyhalcone (10) and is also estimated to be about ten times faster than that of the reactive monoanion of 2',4'-dihydroxychalcone.These are the first calculations of the enhancement of rate of monoanion cyclisation by the 6'-OH group.The effect is only small, and is suggested to arise largely from stabilisation of the transition state for ketonisation by hydrogen bonding to enolate oxygen.Other reactivity differences amongst the chalcone monoanions are also discussed.Enthalpy and entropy of activation data are reported for monoanion cyclisation of (1), (2), and (4)-(6).Rate coefficients for the cyclisation of the chalcone monoanions are almost identical for (1)-(4) and (6) in water but not in deuterium oxide: kinetic hydrogen isotope effect (KIE) values are 3.4 (1), 5.7 (2), 4.9 (3), 3.0 (4), 7.5 (5), 2.9 (6), and 5.0 (8).For chalcones (2) and (7), the KIE values of which are both 5.7, the amounts of H versus D incorporation at the flavanone 3-carbon for monoanion cyclisation in H2O/D2O mixtures were established by mass spectroscopy.This gave product (or 'discrimination') isotope effect (PIE) values of 7.9 for (2) and 3.8 for (7), suggesting for (2) but not (7) an inverse effect contribution to KIE from sources other than rate-limiting proton transfer to carbon.Monoanion cyclisation of (1) in D2O was established by 1H n.m.r. as involving almost equal amounts of anti and syn addition of 2'-O- to the enone double bond.Reactivity differences amongst the chalcones for reactions other than monoanion cyclisation are only briefly considered.
- Miles, Christopher O.,Main, Lyndsay
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p. 1623 - 1632
(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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- Photochemical Deoxygenation of an α-Ketol: The Dihydroflavonol-Flavanone Conversion
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Irradiation of optically pure 2,3-trans-3-hydroxyflavanones in anhydrous ethyl acetate leads directly to free phenolic flavanone analogues with complete retention of configuration at C(2).Similarly their methyl ethers give the corresponding flavanones and flavones.The reaction represents the photochemical equivalent of a reduction under Clemmensen conditions.
- Westhuizen, Jan H. van der,Ferreira, Daneel,Roux, David G.
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p. 1003 - 1006
(2007/10/02)
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