Superior anticancer activity of halogenated chalcones and flavonols over the natural flavonol quercetin

Dias, Tatiana A.; Duarte, Cecília L.; Lima, Cristóvão F.; Proença, M. Fernanda; Pereira‐Wilson, Cristina

doi:10.1016/j.ejmech.2013.04.064

Cited by 89 publications

(62 citation statements)

References 39 publications

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“…22-24 Specifically, the intermediate 3′,4′-dimethoxychalcone ( 9 ) was prepared by aldol condensation of 2′-hydroxyacetophenone ( 7 ) with 3,4-dimethoxybenzaldehyde ( 8 ), which was directly subjected to the Algar-Flynne-Oyamada (AFO) reaction without further purification to furnish 3′,4′-dimethoxyflavonol ( 10 ) in 34% overall yield for two steps. Eight 3- O -alkyl-3′,4′-dimethoxyflavonols (11-18) were prepared in 75-99% yields via O -alkylating 3′,4′-dimethoxyflavonol ( 10 ) with an appropriate alkyl iodide or alkyl bromide mediated by potassium carbonate in DMF (Scheme 2).…”

mentioning

confidence: 99%

A new class of flavonol-based anti-prostate cancer agents: Design, synthesis, and evaluation in cell models

Chen

Zhang

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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Flavonoids are a large class of polyphenolic compounds ubiquitously distributed in dietary plants with an array of biological activities. Flavonols are a major sub-class of flavonoids featuring a hydroxyl group at C-3. Certain natural flavonols, such as quercetin and fisetin, have been shown by in vitro cell-based and in vivo animal experiments to be potential anti-prostate cancer agents. However, the Achilles' heel of flavonols as drug candidates is their moderate potency and poor pharmacokinetic profiles. This study aims to explore the substitution effect of 3-OH in flavonols on the in vitro anti-proliferative potency against both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Our first lead flavonol (3′,4′-dimethoxyflavonol), eight 3-O-alkyl-3′,4′-dimethoxyflavonols, and six 3-O-aminoalkyl-3′,4′-dimethoxyflavonols have been synthesized through aldol condensation and the Algar-Flynn-Oyamada (AFO) reaction. The WST-1 cell proliferation assay indicates i) that all synthesized 3-O-alkyl-3′,4′-dimethoxyflavonols and 3-O-aminoalkyl-3′,4′-dimethoxyflavonols are more potent than the parent 3′,4′-dimethoxyflavonol and the natural flavonol quercetin in suppressing prostate cancer cell proliferation; and ii) that incorporation of a dibutylamino group to the 3-OH group through a three- to five-carbon linker leads to the optimal derivatives with up to 292-fold enhanced potency as compared with the parent flavonol. Flow cytometry analysis showed that the most potent derivative 22 can activate PC-3 cell cycle arrest at the G2/M phase and induce PC-3 cell apoptosis. No inhibitory ability of 22 up to 50 μM concentration was observed against PWR-1E normal human epithelial prostate cells, suggesting its in vitro safety profile. The results indicate that chemical modulation at 3-OH is a vital strategy to optimize flavonols as anti-prostate cancer agents.

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confidence: 99%

A new class of flavonol-based anti-prostate cancer agents: Design, synthesis, and evaluation in cell models

Chen

Zhang

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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“…The parent compound, 3′,4′,5′-trimethoxyflavonol ( 3 ), has been synthesized through a well-known two-step procedure for the synthesis of flavonols, 12,13 including formation of chalcone via a Claisen-Schmidt condensation of 2′-hydroxylacetophenone ( 6 ) with 3,4,5-trimethoxylbenzaldehyde ( 7 ) 14 and cyclization of chalcone through Algar-Flynn-Oyamada (AFO) reaction. 15 This two-step procedure has been widely applied to the synthesis of flavonols, but with tedious workup and purification processes, as well as moderate overall yields.…”

Section: Resultsmentioning

confidence: 99%

3-O-Substituted-3′,4′,5′-trimethoxyflavonols: Synthesis and cell-based evaluation as anti-prostate cancer agents

Lee

Chen

et al. 2017

Bioorganic & Medicinal Chemistry

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Twenty-two 3-O-substituted-3′,4′,5′-trimethoxyflavonols have been designed and synthesized for their anti-proliferative activity towards three human prostate cancer cell lines. Our results indicate that most of them are significantly more potent than the parent 3′,4′,5′-trimethoxyflavonol in inhibiting the cell proliferation in PC-3 and LNCaP prostate cancer cell models. 3-O-Substituted-3′,4′,5′-trimethoxyflavonols have generally higher potency towards PC-3 and LNCaP cell lines than the DU145 cell line. Incorporation of an ethyl group to 3-OH of 3′,4′,5′-trimethoxyflavonol leads to 3-O-ethyl-3′,4′,5′-trimethoxyflavonol as the optimal derivative with up to 36-fold enhanced potency as compared with the corresponding lead compound 3′,4′,5′-trimethoxyflavonol, but with reversed PC-3 cell apoptotic response. Introduction of a dipentylaminopropyl group to 3-OH increases not only the antiproliferative potency but also the ability in activating PC-3 cell apoptosis. Our findings imply that modification on 3-OH of trimethoxyflavonol can further enhance its in vitro anti-proliferative potency and PC-3 cell apoptosis induction.

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“…The effect of test compounds for 48 h on cell death by apoptosis in HCT116 cells seeded in 12-multiwell culture plates was evaluated by fluorescence microscopy assessing the presence of nuclear condensation as previously described (Dias et al, 2013). Briefly, both floating and attached cells were collected by trypsin treatment, fixed with 4% (w/v) paraformaldehyde in PBS for 15 min at room temperature.…”

Section: Cell Death By Apoptosismentioning

confidence: 99%

“…Several new chromene-based molecules were synthesized in our group over the last years Costa, 2008, 2010;Dias et al, 2013). Some of these structures are analogous to a number of anticancer natural chromene derivatives and, therefore, we expect them to be promising drug candidates.…”

Section: Introductionmentioning

confidence: 99%

Novel structurally similar chromene derivatives with opposing effects on p53 and apoptosis mechanisms in colorectal HCT116 cancer cells

Lima

Costa

Proença

et al. 2015

European Journal of Pharmaceutical Sciences

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Superior anticancer activity of halogenated chalcones and flavonols over the natural flavonol quercetin

Cited by 89 publications

References 39 publications

A new class of flavonol-based anti-prostate cancer agents: Design, synthesis, and evaluation in cell models

A new class of flavonol-based anti-prostate cancer agents: Design, synthesis, and evaluation in cell models

3-O-Substituted-3′,4′,5′-trimethoxyflavonols: Synthesis and cell-based evaluation as anti-prostate cancer agents

Novel structurally similar chromene derivatives with opposing effects on p53 and apoptosis mechanisms in colorectal HCT116 cancer cells

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