- A novel one-pot synthesis of flavones
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In this paper, a one-pot facile route for the BiCl3/RuCl3-mediated synthesis of functionalized flavones is described, including: (i) intermolecularortho-acylation of substituted phenols with cinnamoyl chlorides, and (ii) intramolecular cyclodehydrogenation of the resultingo-hydroxychalcones. The reaction conditions are discussed herein.
- Chang, Meng-Yang,Tsai, Min-Chen,Lin, Chun-Yi
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p. 11655 - 11662
(2021/03/31)
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- Biotransformation of 5,7-Methoxyflavones by Selected Entomopathogenic Filamentous Fungi
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5,7-Dimethoxyflavone, a chrysin derivative, occurs in many plants and shows very low toxicity, even at high doses. On the basis of this phenomenon, we biotransformed a series of methoxy-derivatives of chrysin, apigenin, and tricetin obtained by chemical synthesis. We used entomopathogenic fungal strains with the confirmed ability of simultaneous hydroxylation/demethylation and glycosylation of flavonoid compounds. Both the amount and the place of attachment of the methoxy group influenced the biotransformation rate and the product's amount nascent. Based on product and semi-product structures, it can be concluded that they are the result of cascading transformations. Only in the case of 5,7,3′,4′,5′-pentamethoxyflavone, the strains were able to attach a sugar molecule in place of the methoxy substituent to give 3′-O-β-d-(4″-O-methylglucopyranosyl)-5,7,4′,5′-tetramethoxyflavone. However, we observed the tested strains' ability to selectively demethylate/hydroxylate the carbon C-3′ and C-4′ of ring B of the substrates used. The structures of four hydroxyl-derivatives were determined: 4′-hydroxy-5,7-dimethoxyflavone, 3′-hydroxy-5,7-dimethoxyflavone, 3′-hydroxy-5,7,4′,5′-tetramethoxyflavone, and 5,7-dimethoxy-3′,4′-dihydroxyflavone (5,7-dimethoxy-luteolin).
- ?u?ny, Mateusz,Tronina, Tomasz,Koz?owska, Ewa,Kostrzewa-Sus?ow, Edyta,Janeczko, Tomasz
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p. 3879 - 3886
(2021/05/04)
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- Discovery of polymethoxyflavones as potential cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and phosphodiesterase 4B (PDE4B) inhibitors
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Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed to treat inflammatory-related diseases, pain and fever. However, the prolong use of traditional NSAIDs leads to undesirable side effects such as gastric, ulceration, and renal toxicity due to lack of selectivity toward respective targets for COX-2, 5-LOX, and PDE4B. Thus, targeting multiple sites can reduce these adverse effects of the drugs and increase its potency. A series of methoxyflavones (F1–F5) were synthesized and investigated for their anti-inflammatory properties through molecular docking and inhibition assays. Among these flavones, only F2 exhibited selectivity toward COX-2 (Selectivity Index, SI: 3.90, COX-2 inhibition: 98.96 ± 1.47%) in comparison with celecoxib (SI: 7.54, COX-2 inhibition: 98.20 ± 2.55%). For PDEs, F3 possessed better selectivity to PDE4B (SI: 4.67) than rolipram (SI: 0.78). F5 had the best 5-LOX inhibitory activity among the flavones (33.65 ± 4.74%) but less than zileuton (90.81 ± 0.19%). Docking analysis indicated that the position of methoxy group and the substitution of halogen play role in determining the bioactivities of flavones. Interestingly, F1–F5 displayed favorable pharmacokinetic profiles and acceptable range of toxicity (IC50>70 μM) in cell lines with the exception for F1 (IC50: 16.02 ± 1.165 μM). This study generated valuable insight in designing new anti-inflammatory drug based on flavone scaffold. The newly synthesized flavones can be further developed as future therapeutic agents against inflammation.
- Hamzah, Ahmad Sazali,Md Idris, Muhd Hanis,Mohd Amin, Siti Norhidayah,Mohd Amin, Siti Norhidayu,Salleh, Mohd Zaki,Selvaraj, Manikandan,Shaameri, Zurina,Teh, Lay Kek,Wibowo, Agustono,Zakaria, Zainul Amiruddin
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- Chalcone methoxy derivatives exhibit antiproliferative and proapoptotic activity on canine lymphoma and leukemia cells
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Chalcones are interesting candidates for anti-cancer drugs due to the ease of their synthesis and their extensive biological activity. The study presents antitumor activity of newly synthesized chalcone analogues with a methoxy group on a panel of canine lymphoma and leukemia cell lines. The antiproliferative effect of the 20-hydroxychalcone and its methoxylated derivatives was evaluated in MTT assay after 48 h of treatment in different concentrations. The proapoptotic activity was studied by cytometric analysis of cells stained with Annexin V/FITC and propidium iodide and by measure caspases 3/7 and 8 activation. The DNA damage was evaluated by Western blot analysis of phosphorylated histone H2AX. The new compounds had selective antiproliferative activity against the studied cell lines, the most effective were the 20-hydroxy-200,500-dimethoxychalcone and 20-hydroxy-40,60-dimethoxychalcone. 20-Hydroxychalcone and the two most active derivatives induced apoptosis and caspases participation, but some percentage of necrotic cells was also observed. Comparing phosphatidylserine externalization after treatment with the different compounds it was noted that the addition of two methoxy groups increased the proapoptotic potential. The most active compounds triggered DNA damage even in the cell lines resistant to chalcone-induced apoptosis. The results confirmed that the analogues could have anticancer potential in the treatment of canine lymphoma or leukemia.
- ?uz?ny, Mateusz,Henklewska, Marta,Janeczko, Tomasz,Koz?owska, Ewa,Obmińska-Mrukowicz, Bozena,Pawlak, Aleksandra,Suárez, Beatriz Hernández
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- Attrition-enhanced deracemization and absolute asymmetric synthesis of flavanones from prochiral precursors
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Seven racemic 5,7-dimethoxyflavanones afforded conglomerate crystals upon recrystallization from a solvent. Three methodologies were investigated to achieve asymmetric transformation based on dynamic crystallization of the chiral conglomerate system. The first was chiral symmetry breaking of racemic flavanones by attrition-enhanced deracemization. Continuous suspension of racemic flavanones in a small amount of propanol in the presence of a base (1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) and glass beads promoted chiral symmetry breaking and converted the flavanones to crystals of (+)- or (-)-enantiomers with 78 to 99% ee. The second method involved cyclization of the intermediate aldol product to give optically active flavanone with 90% ee involving a reversible oxa-Michael addition reaction with attrition-enhanced deracemization. The third was a reaction starting from prochiral 2-hydroxy-4,6-dimethoxyacetophenone and 2-naphthaldehyde under basic conditions, which gave the corresponding flavanone in 89% ee.
- Kasashima, Yoshio,Mino, Takashi,Sakamoto, Masami,Shimizu, Waku,Uemura, Naohiro,Yoshida, Yasushi
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p. 5676 - 5681
(2020/10/13)
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- Enzyme-assisted cyclization of chalcones to flavanones
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Enzyme catalyzed synthesis is an eco-friendly technique in organic synthesis, having several benefits over conventional methods. In the present work, we describe a simple process of laccase and chloroperoxidase assisted cyclization of chalcones, leading to the formation of flavanones. The reaction proceeds in a mixture of phosphate buffer and ethanol, under oxygen atmosphere at room temperature, yielding the corresponding flavanone in good to moderate yield. The relative configuration of the products at C2 is tentatively assigned as S*-flavanone based on the coupling constants with the methylenic protons H3α,β. In comparison to the chemical methods, we describe a process which can be achieved efficiently under mild conditions using oxygen as oxidant.
- Alonso, Mariana Macías,Boluda, Carlos José,Barajas, Gabriela Díaz,Sánchez, Nallely Caldera,Córdova-Guerrero, Iván,Marrero, Joaquín González
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p. 926 - 931
(2020/12/23)
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- In Vitro Osteogenic Differentiation and Antibacterial Potentials of Chalcone Derivatives
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Chalcone derivatives have been investigated as therapeutic agents for the anticancer, antioxidant, and anti-inflammatory fields. In this study, we have synthesized four different types of chalcone derivatives and demonstrated in vitro bioactivities. We divided these derivatives into two groups of chalcones on the basis of similar substituents on the aromatic rings, and we tested cell viability and proliferation potentials, which indicated that the methoxy substituent on the A ring could enhance cytotoxicity and antiproliferation potential depending on the chalcone concentration. We also investigated osteogenic differentiation of C2C12 cells by ALP staining, the early marker for osteogenesis, which demonstrated that the chalcones could not only induce activity of BMP-2 but also inhibit the activity of noggin, a BMP antagonist. In addition, chalcone bearing hydroxyl groups at the 2-, 4-, and 6-position on the A ring inhibited treptococcus mutans growth, a major causative agent of dental caries. Therefore, we concluded that the chalcone derivatives synthesized in this research can be good candidates for therapeutic agents promoting bone differentiation, with an expectation of inhibiting S. mutans, in dentistry.
- Choi, Daheui,Park, Jin Chan,Lee, Ha Na,Moon, Ji-Hoi,Ahn, Hyo-Won,Park, Kwangyong,Hong, Jinkee
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p. 3197 - 3204
(2018/07/25)
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- 2-substituted benzopyran-4-one compounds and application thereof
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The invention relates to the technical field of medicine and discloses 2-substituted benzopyran-4-one compounds with a structure shown in general formula I and an application of the compounds in preparation of antifungal drugs and synergistic antifungal drugs. The compounds can be jointly used with azole antifungal drugs, can improve sensibility of drug-resistance bacteria to the azole drugs, reverses drug resistance and produces a synergistic antifungal function.
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Paragraph 0173
(2016/10/08)
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- Pro-angiogenic effects of chalcone derivatives in zebrafish embryos in vivo
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The aim of this study was to investigate novel chalcones with potent angiogenic activities in vivo. Chalcone-based derivatives were evaluated using a transgenic zebrafish line with fluorescent vessels to real-time monitor the effect on angiogenesis. Results showed that the chalcone analogues did not possess anti-angiogenic effect on zebrafish vasculatures; instead, some of them displayed potent pro-angiogenic effects on the formation of the sub-intestinal vein. Similar pro-angiogenic effects can also be seen on wild type zebrafish embryos. Moreover, the expression of vegfa, the major regulator for angiogenesis, was also upregulated in their treatment. Taken together, we have synthesized and identified a series of novel chalcone-based derivatives as potent in vivo pro-angiogenic compounds. These novel compounds hold potential for therapeutic angiogenesis.
- Chen, Yau-Hung,Chang, Chao-Yuan,Chang, Chiung-Fang,Chen, Po-Chih,Lee, Ya-Ting,Chern, Ching-Yuh,Tsai, Jen-Ning
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p. 12512 - 12524
(2015/08/06)
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- Development of a concise synthesis of the flavonoid chrysin
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Two novel routes for the synthesis of the flavonoid chrysin are described. In the first, 3,5-dimethoxyphenol (taxicatigenin) was converted to 2-hydroxy-4,6-dimethoxyacetophenone and then by condensation with benzaldehyde to 2'-hydroxy-4',6'-dimethoxychalcone. The latter was cyclised with iodine and demethylated with pyridine hydrochloride to form chrysin in 50% overall yield. In the second route, taxicatigenin was acylated with cinnamoyl chloride to form a chalcone under special conditions. This was then converted to chrysin in 42% and 56% overall yield, respectively. Several disadvantages of previous syntheses like long reaction time, tedious work-up and low overall yield have been overcome.
- Wang, Qian,Cui, Wei,Yang, Jian,Yang, Bo
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p. 300 - 302
(2015/06/02)
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- Flavokawain derivative or pharmaceutically acceptable salt thereof having inhibitory activity on Hsp90 and medical use thereof
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The present invention relates to a flavokawain derivative or a pharmaceutically acceptable salt thereof having an activity for inhibiting Hsp90 and a medical use thereof wherein the flavokawain derivative comprises good effect of inhibiting Hsp90 and accordingly leads to decomposition of Hsp 90 client protein causing diseases related to cancer or neurodegenerative diseases by inhibiting Hsp90, thereby being used in drug medicine and healthy food products for preventing or treating Hsp 90 which is a mediated disease like diseases related to cancer or neurodegenerative diseases.COPYRIGHT KIPO 2015
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Paragraph 0073-0077
(2016/10/10)
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- Synthesis and acetylcholinesterase inhibitory activity of Mannich base derivatives flavokawain B
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A novel series of flavokawain B derivatives, chalcone Mannich bases (4-10) were designed, synthesized, characterized, and evaluated for the inhibition activity against acetylcholinesterase (AChE). Biological results revealed that four compounds displayed potent activities against AChE with IC50values below 20 μM. Moreover, the most promising compound 8 was 2-fold more active than rivastigmine, a well-known AChE inhibitor. The log P values of 4-10 were around 2 which indicated that they were sufficiently lipophilic to pass blood brain barriers in vivo. Enzyme kinetic study suggested that the inhibition mechanism of compound 8 was a mixed-type inhibition. Meanwhile, the molecular docking showed that this compound can both bind with the catalytic site and the periphery of AChE.
- Liu, Hao-Ran,Huang, Xue-Qin,Lou, Ding-Hui,Liu, Xian-Jun,Liu, Wu-Kun,Wang, Qiu-An
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p. 4749 - 4753
(2015/01/16)
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- An efficient synthesis of chrysin
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Two routes for the synthesis of the flavones chrysin are described. In the first 1,3,5-trimethoxybenzene was converted to 2-hydroxy-4,6- dimethoxyacetophenone and then by condensation with benzaldehyde to 2′-hydroxy-4′,6′-dimethoxychalcone. The latter was cyclised with iodine and demethylated with pyridine hydrochloride to form chrysin in 53% overall yield. In the second route, 1,3,5-trimethoxybenzene was acylated with cinnamic acid to form the chalcone which was then converted to chrysin in 30.7% overall yield.
- Liu, Man,Zhang, Ji,Yang, Jian,Yang, Bo,Cui, Wei
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p. 134 - 136
(2014/04/17)
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- Aurones as histone deacetylase inhibitors: Identification of key features
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In this study, a total of 22 flavonoids were tested for their HDAC inhibitory activity using fluorimetric and BRET-based assays. Four aurones were found to be active in both assays and showed IC50 values below 20 μM in the enzymatic assay. Molecular modelling revealed that the presence of hydroxyl groups was responsible for good compound orientation within the isoenzyme catalytic site and zinc chelation.
- Zwick, Vincent,Chatzivasileiou, Alkiviadis-Orfefs,Deschamps, Nathalie,Roussaki, Marina,Simes-Pires, Claudia A.,Nurisso, Alessandra,Denis, Iza,Blanquart, Christophe,Martinet, Nadine,Carrupt, Pierre-Alain,Detsi, Anastasia,Cuendet, Muriel
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supporting information
p. 5497 - 5501
(2014/12/12)
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- Intermolecular C-O addition of carboxylic acids to arynes: Synthesis of o-hydroxyaryl ketones, xanthones, 4-chromanones, and flavones
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An efficient and simple route to biologically and pharmaceutically important o-hydroxyaryl ketones, xanthones, 4-chromanones, and flavones has been developed utilizing readily available carboxylic acids and commercially available o-(trimethylsilyl)aryl tr
- Dubrovskiy, Anton V.,Larock, Richard C.
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p. 2789 - 2798
(2013/03/29)
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- Synthesis, structure-activity relationship analysis and kinetics study of reductive derivatives of flavonoids as Helicobacter pylori urease inhibitors
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In a continuing study for discovering urease inhibitors based on flavonoids, nineteen reductive derivatives of flavonoids were synthesized and evaluated against Helicobacter pylori urease. Analysis of structure-activity relationship disclosed that 4-deoxy analogues are more potent than other reductive products. Out of them, 4′,7,8-trihydroxyl-2-isoflavene (13) was found to be the most active with IC50 of 0.85 μM, being over 20-fold more potent than the commercial available urease inhibitor, acetohydroxamic acid (AHA). Kinetics study revealed that 13 is a competitive inhibitor of H. pylori urease with a Ki value of 0.641 μM, which is well matched with the results of molecular docking. Biological evaluation and mechanism study of 13 suggest that it is a good candidate for discovering novel anti-gastritis and anti-gastric ulcer agent.
- Xiao, Zhu-Ping,Peng, Zhi-Yun,Dong, Jing-Jun,He, Juan,Ouyang, Hui,Feng, Yu-Ting,Lu, Chun-Lei,Lin, Wan-Qiang,Wang, Jin-Xiang,Xiang, Yin-Ping,Zhu, Hai-Liang
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p. 685 - 695
(2013/07/25)
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- A synthetic chalcone as a potent inducer of glutathione biosynthesis
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Chalcones continue to attract considerable interest due to their anti-inflammatory and antiangiogenic properties. We recently reported the ability of 2′,5′-dihydroxychalcone (2′,5′-DHC) to induce both breast cancer resistance protein-mediated export of glutathione (GSH) and c-Jun N-terminal kinase-mediated increased intracellular GSH levels. Herein, we report a structure-activity relationship study of a series of 30 synthetic chalcone derivatives with hydroxyl, methoxyl, and halogen (F and Cl) substituents and their ability to increase intracellular GSH levels. This effect was drastically improved with one or two electrowithdrawing groups on phenyl ring B and up to three methoxyl and/or hydroxyl groups on phenyl ring A. The optimal structure, 2-chloro-4′,6′-dimethoxy-2′- hydroxychalcone, induced both a potent NF-E2-related factor 2-mediated transcriptional response and an increased formation of glutamate cysteine ligase holoenzyme, as shown using a human breast cancer cell line stably expressing a luciferase reporter gene driven by antioxidant response elements.
- Kachadourian, Remy,Day, Brian J.,Pugazhenti, Subbiah,Franklin, Christopher C.,Genoux-Bastide, Estelle,Mahaffey, Gregory,Gauthier, Charlotte,Di Pietro, Attilio,Boumendjel, Ahcène
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experimental part
p. 1382 - 1388
(2012/04/04)
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- Investigation of chalcones as selective inhibitors of the breast cancer resistance protein: Critical role of methoxylation in both inhibition potency and cytotoxicity
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ABCG2 plays a major role in anticancer-drug efflux and related tumor multidrug resistance. Potent and selective ABCG2 inhibitors with low cytotoxicity were investigated among a series of 44 chalcones and analogues (1,3-diarylpropenones), by evaluating their inhibitory effect on the transport of mitoxantrone, a known ABCG2 substrate. Six compounds producing complete inhibition with IC50 values below 0.5 μM and high selectivity for ABCG2 were identified. The number and position of methoxy substituents appeared to be critical for both inhibition and cytotoxicity. The best compounds, with potent inhibition and low toxicity, contained an N-methyl-1-indolyl (compound 38) or a 6′-hydroxyl-2′,4′-dimethoxy-1-phenyl (compound 27) moiety (A-ring) and two methoxy groups at positions 2 and 6 of the 3-phenyl moiety (B-ring). Methoxy substitution contributed to inhibition at positions 3 and 5, but had a negative effect at position 4. Finally, methoxy groups at positions 3, 4, and 5 of the B-ring markedly increased cytotoxicity and, therefore, should be avoided.
- Valdameri, Glaucio,Gauthier, Charlotte,Terreux, Rapha?l,Kachadourian, Rémy,Day, Brian J.,Winnischofer, Sheila M. B.,Rocha, Maria E. M.,Frachet, Véronique,Ronot, Xavier,Di Pietro, Attilio,Boumendjel, Ahcène
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scheme or table
p. 3193 - 3200
(2012/06/01)
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- Synthesis of a Range of Polyhydroxy 8-Aryl Flavones
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The 8-iodo flavones formed by cyclization of benzyl-protected chalcones with iodine in dimethyl sulfoxide have been transformed by a Suzuki coupling reaction into a variety of 8-aryl derivatives. Deprotection with boron tribromide has generated a family of new 8-aryl flavones containing four to eight hydroxyl groups.
- Larsen, Lesley,Yoon, Dong Hee,Weavers, Rex T.
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experimental part
p. 2935 - 2948
(2009/12/03)
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- Structure - Activity relationship studies of chalcone leading to 3-hydroxy-4,3′,4′,5′-tetramethoxychalcone and its analogues as potent nuclear factor κB inhibitors and their anticancer activities
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Chalcone is a privileged structure, demonstrating promising anti-inflammatory and anticancer activities. One potential mechanism is to suppress nuclear factor kappa B (NF-κB) activation. The structures of chalcone-based NF-κB inhibitors vary significantly that there is minimum information about their structure-activity relationships (SAR). This study aims to establish SAR of chalcone-based compounds to NF-κB inhibition, to explore the feasibility of developing simple chalcone-based potent NF-κB inhibitors, and to evaluate their anticancer activities. Three series of chalcones were synthesized in one to three steps with the key step being aldol condensation. These candidates demonstrated a wide range of NF-κB inhibitory activities, some of low micromolar potency, establishing that structural complexity is not required for NF-κB inhibition. Lead compounds also demonstrate potent cytotoxicity against lung cancer cells. Their cytotoxicities correlate moderately well with their NF-κB inhibitory activities, suggesting that suppressing NF-κB activation is likely responsible for at least some of the cytotoxicities. One lead compound effectively inhibits lung tumor growth with no signs of adverse side effects.
- Srinivasan, Balasubramanian,Johnson, Thomas E.,Lad, Rahul,Xing, Chengguo
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experimental part
p. 7228 - 7235
(2010/08/19)
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- Antispasmodic activity of xanthoxyline derivatives: Structure-activity relationships
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The antispasmodic activity of several xanthoxyline derivatives against acetylcholine-induced contraction of the guinea pig ileum was evaluated in vitro. The acetophenones with two methoxyl groups, mainly in the 3,4 positions, exhibited potent antispasmodic activity. Modification of the hydroxyl group in xanthoxyline by the introduction of benzoyl, acetyl, or tosyl groups produced inactive compounds, whereas the introduction of benzyl or p-methoxybenzyl groups furnished compounds that were four- to eight-fold more potent than xanthoxyline. In marked contrast, the introduction of a methyl group gave a compound that caused contractant activity. Modification of the carbonyl group of xanthoxyline lead to inactive compounds, whereas the condensation of xanthoxyline with benzaldehydes gave chalkones that were about fivefold more potent than xanthoxyline. The introduction of benzyl and styrene groups, on the basis of the similarity with papaverine, improves the antispasmodic action of the xanthoxyline derivatives. Our results suggest that the methoxyl and carbonyl groups are critical structural points for the antispasmodic activity of xanthoxyline derivatives. The hydroxyl group improves antispasmodic activity, but is not fundamental to its manifestation.
- Filho,Miguel,Nunes,Calixto,Yunes
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p. 473 - 475
(2007/10/02)
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- Dye-sensitized Photo-oxygenation of Chalcones
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The dye-sensitized photo-oxygenation of several chalcones has been examined.Some of the chalcones give rise to degradation products while others lead to flavonol formation.A rational explanation for the observations has been proposed.The study may have a significance in the biogenesis of naturally occurring plant polyphenolics.
- Chawla, H. Mohindra,Chakrabarty, Kakoli
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p. 1511 - 1513
(2007/10/02)
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