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Quinoxaline-substituted chalcones as new inhibitors of breast cancer resistance protein ABCG2: polyspecificity at B-ring position.

Winter E, Gozzi GJ, Chiaradia-Delatorre LD, Daflon-Yunes N, Terreux R, Gauthier C, Mascarello A, Leal PC, Cadena SM, Yunes RA, Nunes RJ, Creczynski-Pasa TB, Di Pietro A - Drug Des Devel Ther (2014)

Bottom Line: In all cases, two or three methoxy groups had to be present on the phenyl A-ring to produce a maximal inhibition.Molecular modeling indicated both electrostatic and steric positive contributions.A higher potency was observed when the 2-naphthyl or 3,4-methylenedioxyphenyl group was shifted to the A-ring and methoxy substituents were shifted to the phenyl B-ring, indicating preferences among polyspecificity of inhibition.

View Article: PubMed Central - PubMed

Affiliation: Equipe Labellisée Ligue 2013, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France ; Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianopolis, Brazil.

ABSTRACT
A series of chalcones substituted by a quinoxaline unit at the B-ring were synthesized and tested as inhibitors of breast cancer resistance protein-mediated mitoxantrone efflux. These compounds appeared more efficient than analogs containing other B-ring substituents such as 2-naphthyl or 3,4-methylenedioxyphenyl while an intermediate inhibitory activity was obtained with a 1-naphthyl group. In all cases, two or three methoxy groups had to be present on the phenyl A-ring to produce a maximal inhibition. Molecular modeling indicated both electrostatic and steric positive contributions. A higher potency was observed when the 2-naphthyl or 3,4-methylenedioxyphenyl group was shifted to the A-ring and methoxy substituents were shifted to the phenyl B-ring, indicating preferences among polyspecificity of inhibition.

No MeSH data available.


Related in: MedlinePlus

Synthesis of quinoxaline-substituted chalcones.Notes: (A) Step 1: selenium dioxide, 180°C, 3 hours; step 2: 210–230°C, 3–4 minutes. (B) Corresponding acetophenone, 50% potassium hydroxide, methanol, room temperature, 24 hours. *Represents novel compounds.
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f1-dddt-8-609: Synthesis of quinoxaline-substituted chalcones.Notes: (A) Step 1: selenium dioxide, 180°C, 3 hours; step 2: 210–230°C, 3–4 minutes. (B) Corresponding acetophenone, 50% potassium hydroxide, methanol, room temperature, 24 hours. *Represents novel compounds.

Mentions: All reagents were purchased from Sigma-Aldrich (St Louis, MO, USA) or Oakwood Products (West Columbia, NC, USA), and solvents from Merck (Whitehouse Station, NJ, USA) or Vetec (Duque de Caxias, RJ, Brazil). The quinoxaline-6-carbaldehyde was synthesized directly from the methyl-quinoxaline as previously described,21 with a yield of 80%. The quinoxaline-substituted chalcones (1–12) were prepared by aldol condensation between quinoxaline-6-carbaldehyde and corresponding acetophenones in methanol and potassium hydroxide 50% w/v, under magnetic stirring at room temperature (Figure 1). Distilled water and 10% hydrochloric acid were added to the reaction for total precipitation of the compounds, which were then obtained by vacuum filtration and recrystallized in dichloromethane/hexane or ethanol. The purity of the synthesized compounds was analyzed by thin-layer chromatography using Merck silica-precoated aluminum plates of 200 μm thickness, with a hexane/ethyl acetate 1:1 system. Compounds were visualized with ultraviolet light (λ=254 nm and 360 nm) and using sulfuric anisaldehyde solution followed by heat application as the developing agent. Compounds 1–4 were previously published by our group,22 and 5–12 were newly synthesized chalcones obtained with yields between 79% and 92%.


Quinoxaline-substituted chalcones as new inhibitors of breast cancer resistance protein ABCG2: polyspecificity at B-ring position.

Winter E, Gozzi GJ, Chiaradia-Delatorre LD, Daflon-Yunes N, Terreux R, Gauthier C, Mascarello A, Leal PC, Cadena SM, Yunes RA, Nunes RJ, Creczynski-Pasa TB, Di Pietro A - Drug Des Devel Ther (2014)

Synthesis of quinoxaline-substituted chalcones.Notes: (A) Step 1: selenium dioxide, 180°C, 3 hours; step 2: 210–230°C, 3–4 minutes. (B) Corresponding acetophenone, 50% potassium hydroxide, methanol, room temperature, 24 hours. *Represents novel compounds.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043709&req=5

f1-dddt-8-609: Synthesis of quinoxaline-substituted chalcones.Notes: (A) Step 1: selenium dioxide, 180°C, 3 hours; step 2: 210–230°C, 3–4 minutes. (B) Corresponding acetophenone, 50% potassium hydroxide, methanol, room temperature, 24 hours. *Represents novel compounds.
Mentions: All reagents were purchased from Sigma-Aldrich (St Louis, MO, USA) or Oakwood Products (West Columbia, NC, USA), and solvents from Merck (Whitehouse Station, NJ, USA) or Vetec (Duque de Caxias, RJ, Brazil). The quinoxaline-6-carbaldehyde was synthesized directly from the methyl-quinoxaline as previously described,21 with a yield of 80%. The quinoxaline-substituted chalcones (1–12) were prepared by aldol condensation between quinoxaline-6-carbaldehyde and corresponding acetophenones in methanol and potassium hydroxide 50% w/v, under magnetic stirring at room temperature (Figure 1). Distilled water and 10% hydrochloric acid were added to the reaction for total precipitation of the compounds, which were then obtained by vacuum filtration and recrystallized in dichloromethane/hexane or ethanol. The purity of the synthesized compounds was analyzed by thin-layer chromatography using Merck silica-precoated aluminum plates of 200 μm thickness, with a hexane/ethyl acetate 1:1 system. Compounds were visualized with ultraviolet light (λ=254 nm and 360 nm) and using sulfuric anisaldehyde solution followed by heat application as the developing agent. Compounds 1–4 were previously published by our group,22 and 5–12 were newly synthesized chalcones obtained with yields between 79% and 92%.

Bottom Line: In all cases, two or three methoxy groups had to be present on the phenyl A-ring to produce a maximal inhibition.Molecular modeling indicated both electrostatic and steric positive contributions.A higher potency was observed when the 2-naphthyl or 3,4-methylenedioxyphenyl group was shifted to the A-ring and methoxy substituents were shifted to the phenyl B-ring, indicating preferences among polyspecificity of inhibition.

View Article: PubMed Central - PubMed

Affiliation: Equipe Labellisée Ligue 2013, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France ; Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianopolis, Brazil.

ABSTRACT
A series of chalcones substituted by a quinoxaline unit at the B-ring were synthesized and tested as inhibitors of breast cancer resistance protein-mediated mitoxantrone efflux. These compounds appeared more efficient than analogs containing other B-ring substituents such as 2-naphthyl or 3,4-methylenedioxyphenyl while an intermediate inhibitory activity was obtained with a 1-naphthyl group. In all cases, two or three methoxy groups had to be present on the phenyl A-ring to produce a maximal inhibition. Molecular modeling indicated both electrostatic and steric positive contributions. A higher potency was observed when the 2-naphthyl or 3,4-methylenedioxyphenyl group was shifted to the A-ring and methoxy substituents were shifted to the phenyl B-ring, indicating preferences among polyspecificity of inhibition.

No MeSH data available.


Related in: MedlinePlus