Synthesis of a Complete Series of O-Methyl Analogues of Naringenin and Apigenin

Kim, Jin‐Young; Park, Kwang‐Su; Lee, Chaewoon; Chang, You-Hoon

doi:10.5012/bkcs.2007.28.12.2527

Cited by 21 publications

(5 citation statements)

References 6 publications

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“…Furthermore, the substitution of O -alkyl chains at the C-7 and C-4′ positions of the naringenin molecule was confirmed by the presence of only one singlet at 12.02–12.01 ppm, originating from the hydroxyl group at the C-5 position. The regioselectivity of the above alkylation reaction of naringenin was generally described in scientific reports [25,26]. In our investigation, one novel tri- O -alkyl derivative was obtained, namely 5,7,4′-tri- O -propylnaringenin ( 9a ).…”

Section: Resultsmentioning

confidence: 60%

Novel O-alkyl Derivatives of Naringenin and Their Oximes with Antimicrobial and Anticancer Activity

et al. 2019

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In our investigation, we concentrated on naringenin (NG)—a widely studied flavanone that occurs in citrus fruits. As a result of a reaction with a range of alkyl iodides, 7 novel O-alkyl derivatives of naringenin (7a–11a, 13a, 17a) were obtained. Another chemical modification led to 9 oximes of O-alkyl naringenin derivatives (7b–13b, 16b–17b) that were never described before. The obtained compounds were evaluated for their potential antibacterial activity against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. The results were reported as the standard minimal inhibitory concentration (MIC) values and compared with naringenin and its known O-alkyl derivatives. Compounds 4a, 10a, 12a, 14a, 4b, 10b, 11b, and 14b were described with MIC of 25 µg/mL or lower. The strongest bacteriostatic activity was observed for 7-O-butylnaringenin (12a) against S. aureus (MIC = 6.25 µg/mL). Moreover, the antitumor effect of flavonoids was examined on human colon cancer cell line HT-29. Twenty-six compounds were characterized as possessing an antiproliferative activity stronger than that of naringenin. The replacement of the carbonyl group with an oxime moiety significantly increased the anticancer properties. The IC50 values below 5 µg/mL were demonstrated for four oxime derivatives (8b, 11b, 13b and 16b).

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Section: Resultsmentioning

confidence: 60%

Novel O-alkyl Derivatives of Naringenin and Their Oximes with Antimicrobial and Anticancer Activity

et al. 2019

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“…Compounds 2a and 2b were the key intermediates for the synthesis of the target compounds. They were prepared from alkylation of 7-hydroxy group using excessive amounts of 1,2-dibromoethane or 1,3-dibromopropane in the presence of potassium carbonate (K 2 CO 3 ) as base in anhydrous N,N -dimethylformamide (DMF) at 120 °C for 2 h [17,18,19,20]. To increase the biological activities of apigenin, we synthesized apigenin derivatives, in which the apigenin ring system was linked to the alkyl amines moieties by different spacers at C-7 position to enhance their lipophilicity.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Apigenin Derivatives as Antibacterial and Antiproliferative Agents

et al. 2013

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Two series of apigenin [5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one] derivatives, 3a-3j and 4a-4j, were synthesized. The apigenin and alkyl amines moieties of these compounds were separated by C 2 or C 3 spacers, respectively. The chemical structures of the apigenin derivatives were confirmed using 1 H-NMR, 13 C-NMR, and electrospray ionization mass spectroscopy. The in vitro antibacterial and antiproliferative activities of all synthesized compounds were determined. Among the tested compounds, 4a-4j displayed significant antibacterial activity against the tested strains (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa). Additionally, 4i showed the best inhibitory activity with minimum inhibitory concentrations of 1.95, 3.91, 3.91, and 3.91 μg/mL against S. aureus, B. subtilis, E. coli, and P. aeruginosa, respectively. The antiproliferative activity of the apigenin derivatives was evaluated by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. We determined that 4a-4j displayed better growth inhibition activity against four human cancer cell lines, namely, human lung (A549), human cervical (HeLa), human hepatocellular liver (HepG2), and human breast (MCF-7) cancer cells, than the parent apigenin. Compound 4j was found to be the most active antiproliferative compound against the selected cancer cells. Structure-activity relationships were also discussed based on the obtained experimental data.

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“…(±)-Naringenin, naringenin 7-O-methyl ether, kaempferol, and kaempferide (4′-O-methyl kaempferol) were purchased (analytical standard, Sigma-Aldrich). Naringenin 4′,7-dimethyl ether was synthesized as previously described (Kim et al, 2007). For experiments with zebrafish larvae, dry samples were dissolved in 100 % dimethyl sulfoxide (DMSO, spectroscopy grade) as 100-fold concentrated stocks and diluted in embryo medium to a final concentration of 1 % DMSO content.…”

Section: Compound Preparation and Calculated Logp Valuesmentioning

confidence: 99%

Methylated flavonoids as anti-seizure agents: Naringenin 4′,7-dimethyl ether attenuates epileptic seizures in zebrafish and mouse models

Copmans

Orellana-Paucar

Steurs

et al. 2018

Neurochemistry International

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Epilepsy is a neurological disease that affects more than 70 million people worldwide and is characterized by the presence of spontaneous unprovoked recurrent seizures. Existing anti-seizure drugs (ASDs) have side effects and fail to control seizures in 30% of patients due to drug resistance. Hence, safer and more efficacious drugs are sorely needed. Flavonoids are polyphenolic structures naturally present in most plants and consumed daily with no adverse effects reported. These structures have shown activity in several seizure and epilepsy animal models through allosteric modulation of GABA receptors, but also via potent anti-inflammatory action in the brain. As such, dietary flavonoids offer an interesting source for ASD and anti-epileptogenic drug (AED) discovery, but their pharmaceutical potential is often hampered by metabolic instability and low oral bioavailability. It has been argued that their drug-likeness can be improved via methylation of the free hydroxyl groups, thereby dramatically enhancing metabolic stability and membrane transport, facilitating absorption and highly increasing bioavailability. Since no scientific data is available regarding the use of methylated flavonoids in the fight against epilepsy, we studied naringenin (NRG), kaempferol (KFL), and three methylated derivatives, i.e., naringenin 7-O-methyl ether (NRG-M), naringenin 4',7-dimethyl ether (NRG-DM), and kaempferide (4'-O-methyl kaempferol) (KFD) in the zebrafish pentylenetetrazole (PTZ) seizure model. We demonstrate that the methylated flavanones NRG-DM and NRG-M are highly effective against PTZ-induced seizures in larval zebrafish, whereas NRG and the flavonols KFL and KFD possess only a limited activity. Moreover, we show that NRG-DM is active in two standard acute mouse seizure models, i.e., the timed i.v. PTZ seizure model and the 6-Hz psychomotor seizure model. Based on these results, NRG-DM is proposed as a lead compound that is worth further investigation for the treatment of generalized seizures and drug-resistant focal seizures. Our data therefore highlights the potential of methylated flavonoids in the search for new and improved ASDs.

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Synthesis of a Complete Series of O-Methyl Analogues of Naringenin and Apigenin

Cited by 21 publications

References 6 publications

Novel O-alkyl Derivatives of Naringenin and Their Oximes with Antimicrobial and Anticancer Activity

Novel O-alkyl Derivatives of Naringenin and Their Oximes with Antimicrobial and Anticancer Activity

Synthesis and Biological Evaluation of Apigenin Derivatives as Antibacterial and Antiproliferative Agents

Methylated flavonoids as anti-seizure agents: Naringenin 4′,7-dimethyl ether attenuates epileptic seizures in zebrafish and mouse models

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