An Effective Synthesis of 5,4'-Disubstituted Flavones via a Cesium Enolate Assisted Intramolecular ipso-Substitution Reaction

Matsugi, Masato; Takeda, Masaki; Takahashi, Ayano; Tazaki, Takahide; Tamura, Hiroto; Shioiri, Takayuki

doi:10.1248/cpb.58.1107

Cited by 13 publications

(3 citation statements)

References 16 publications

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“…1) were rationally selected based on their direct inclusion of a metal binding site into the Aβ interacting scaffold (incorporation approach of rational structure-based design strategy) 2,4,14,19 and prepared following the previously reported methods. [40][41][42] These compounds FL1-FL4 additionally satisfy the restrictive terms of Lipinski's rules and the range of the desired calculated logBB value (Table S1 †), which suggests their potential brain uptake. 53,54 Structurally, the metal binding sites are located at 4oxo and 5-OH or 3-OH groups of FL1, FL2, and FL3, two of the probable binding sites in natural flavonoids.…”

Section: Selection and Preparationmentioning

confidence: 83%

“…All chemical reagents and solvents were purchased from commercial suppliers and used as received unless otherwise specified. 5-Hydroxyflavone (FL1), 40 5-hydroxy-4′-dimethylaminoflavone (FL2), 40 3-hydroxy-4′-dimethylaminoflavone (FL3), 41,42 and 3-hydroxy-2-( pyridin-2-yl)-4H-chromen-4-one (FL4) 42 were prepared following previously reported procedures. Aβ 1-40 peptide (free acid terminal) was purchased from AnaSpec (>95% purity, Fremont, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

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Exploring the reactivity of flavonoid compounds with metal-associated amyloid-β species

Park

Hyung

et al. 2012

Dalton Trans.

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Metal ions associated with amyloid-β (Aβ) peptides have been suggested to be involved in the development of Alzheimer’s disease (AD), but this remains unclear and controversial. Some attempts to rationally design or select small molecules with structural moieties for metal chelation and Aβ interaction (i.e., bifunctionality) have been made to gain a better understanding of the hypothesis. In order to contribute to these efforts, four synthetic flavonoid derivatives FL1 – FL4 were rationally selected according to the principles of bifunctionality and their abilities to chelate metal ions, interact with Aβ, inhibit metal-induced Aβ aggregation, scavenge radicals, and regulate the formation of reactive oxygen species (ROS) were studied using physical methods and biological assays. The compounds FL1 – FL3 were able to chelate metal ions, but showed limited solubility in aqueous buffered solutions. In the case of FL4, which was most compatible with aqueous conditions, its binding affinities for Cu2+ and Zn2+ (nM and μM, respectively) were obtained through solution speciation studies. The direct interaction between FL4 and Aβ monomer was weak, which was monitored by NMR spectroscopy and mass spectrometry. Employing FL1 – FL4, no noticeable inhibitory effect on metal-mediated Aβ aggregation was observed. Among FL1 – FL4, FL3, having 3-OH, 4-oxo, and 4′-N(CH3)2 groups, exhibited similar antioxidant activity to the vitamin E analogue, Trolox, and ca. 60% reduction in the amount of hydrogen peroxide (H2O2) generated by Cu2+-Aβ in the presence of dioxygen (O2) and a reducing agent. Overall, the studies here suggest that although four flavonoid molecules were selected based on expected bifunctionality, their properties and metal-Aβ reactivity were varied depending on the structure differences, demonstrating that bifunctionality must be well tuned to afford desirable reactivity.

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Section: Selection and Preparationmentioning

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Exploring the reactivity of flavonoid compounds with metal-associated amyloid-β species

Park

Hyung

et al. 2012

Dalton Trans.

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“…This crude was then hydrolyzed with a mixture of aqueous HCl (1 N)/ethanol/isopropanol at reflux and then purified by column chromatography using methylene chloride in an isocratic system (100% methylene chloride) as the mobile phase to afford FO7 as a yellow solid (286.9 mg, 59% from chalcone C7 ); mp: 171.2–172.2 °C (lit. [ 31 ] 166–167 °C); HRMS m / z , observed: 287.0738; C 16 H 14 O 3 S [M + H] + requires: 287.0736; IR (KBr): ν max cm −1 : 3447, 3066, 2920, 1651, 1615, 1597, 1582, 1471, 1418, 1361, 1301, 1261, 1229, 1095, 1057, 996, 820, 800, 752. 1 H-NMR (DMSO- d 6 ) δ ppm: 12.70 (s, 1H, ArO H -5); 8.03 (d, 2H, J = 8.6 Hz, Ar H -2′,6′); 7.67 (dd, 1H, J 1 = 8.4 and 8.3 Hz, Ar H -7); 7.42 (d, 2H, J = 8.6 Hz, Ar H -3′,5′); 7.19 (dd, 1H, J 1 = 8.9 and 0.6 Hz, Ar H -8); 7.08 (s, 1H, C H -3); 6.80 (d, 1H, J = 7.7 Hz, Ar H -6); 2.55 (s, 3H, C H 3 S-4′).…”

Section: Methodsmentioning

confidence: 99%

Antibacterial and Antioxidant Activity of Synthetic Polyoxygenated Flavonoids

Osorio-Olivares,

Vásquez-Martínez,

Díaz

et al. 2024

IJMS

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Flavonoids are an abundant class of naturally occurring compounds with broad biological activities, but their limited abundance in nature restricts their use in medicines and food additives. Here we present the synthesis and determination of the antibacterial and antioxidant activities of twenty-two structurally related flavonoids (five of which are new) by scientifically validated methods. Flavanones (FV1–FV11) had low inhibitory activity against the bacterial growth of MRSA 97-7. However, FV2 (C5,7,3′,4′ = OH) and FV6 (C5,7 = OH; C4′ = SCH3) had excellent bacterial growth inhibitory activity against Gram-negative E. coli (MIC = 25 µg/mL for both), while Chloramphenicol (MIC = 25 µg/mL) and FV1 (C5,7,3′ = OCH3; 4′ = OH) showed inhibitory activity against Gram-positive L. monocytogenes (MIC = 25 µg/mL). From the flavone series (FO1–FO11), FO2 (C5,7,3′,4′ = OH), FO3 (C5,7,4′ = OH; 3′ = OCH3), and FO5 (C5,7,4′ = OH) showed good inhibitory activity against Gram-positive MRSA 97-7 (MIC = 50, 12, and 50 µg/mL, respectively), with FO3 being more active than the positive control Vancomycin (MIC = 25 µg/mL). FO10 (C5,7= OH; 4′ = OCH3) showed high inhibitory activity against E. coli and L. monocytogenes (MIC = 25 and 15 µg/mL, respectively). These data add significantly to our knowledge of the structural requirements to combat these human pathogens. The positions and number of hydroxyl groups were key to the antibacterial and antioxidant activities.

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Photocatalyzed Direct α‐Alkylation of Esters Using Styrenes

et al. 2023

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A mild photocatalyzed approach to achieve the α-alkylation of esters via formation of an α -radical is disclosed here. Cesium enolates of esters were generated in situ using Cs 2 CO 3 as a base. A subsequent photocatalyzed oxidation at the α-carbon of these enolates produced an α-radical that was added into activated alkenes. This is the first example accessing the α-carbon radical of esters in photoredox catalyed transformations.

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An Effective Synthesis of 5,4'-Disubstituted Flavones via a Cesium Enolate Assisted Intramolecular ipso-Substitution Reaction

Cited by 13 publications

References 16 publications

Exploring the reactivity of flavonoid compounds with metal-associated amyloid-β species

Exploring the reactivity of flavonoid compounds with metal-associated amyloid-β species

Antibacterial and Antioxidant Activity of Synthetic Polyoxygenated Flavonoids

Photocatalyzed Direct α‐Alkylation of Esters Using Styrenes

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