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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

3D-QSAR analyses.Notes: Structure alignment of the 61 molecules (left panel). CoMSIA contribution volumes from all molecules (right panel); volumes were plotted with 80 for positive contributions (green for steric and blue for electrostatic fields) and 20 for negative contributions (yellow for steric and red for electrostatic fields); the structure of compound 7 is represented.Abbreviations: 3D-QSAR, three dimensional quantitative structure–activity relationship; CoMSIA, comparative molecular similarity index analysis.
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f3-dddt-8-609: 3D-QSAR analyses.Notes: Structure alignment of the 61 molecules (left panel). CoMSIA contribution volumes from all molecules (right panel); volumes were plotted with 80 for positive contributions (green for steric and blue for electrostatic fields) and 20 for negative contributions (yellow for steric and red for electrostatic fields); the structure of compound 7 is represented.Abbreviations: 3D-QSAR, three dimensional quantitative structure–activity relationship; CoMSIA, comparative molecular similarity index analysis.

Mentions: A three dimensional quantitative structure–activity relationship molecular model was constructed after structures alignment from the IC50 values of all compounds, as shown on Figure 3. The positive contribution of quinoxaline at B-ring position (as observed in Table 1) appears to be related to electrostatic interactions of the two nitrogen heteroatoms (blue volumes). The better contribution of 1-naphthyl over 2-naphthyl (as observed in Table 2) might correlate both steric negative effects on the right edge of the site (yellow volume) and electrostatic negative effects on the top (red volume). Concerning methoxy contributions (as observed in Tables 1 and 2), the positive effects appear to be related to steric effects (green volume) at position 2′ and to both steric and electrostatic (blue volume) contributions at positions 4′ and 5′, whereas the negative contribution observed in some cases at position 3′ (such as in 12) as well as negative effects of hydroxyl at position 4′ (in 6 and 10) might be due to electrostatic antagonism (red volume). Other electrostatic negative effects related to B-ring positions 2 and 3 (red volume) appear to correlate the low efficiency of compounds containing hydrophilic substituents such as NO2 (in 37), Cl (in 43, 44, 51, and 58), Br (in 45 and 57), or CF3 (in 40, 42, or 54).


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)

3D-QSAR analyses.Notes: Structure alignment of the 61 molecules (left panel). CoMSIA contribution volumes from all molecules (right panel); volumes were plotted with 80 for positive contributions (green for steric and blue for electrostatic fields) and 20 for negative contributions (yellow for steric and red for electrostatic fields); the structure of compound 7 is represented.Abbreviations: 3D-QSAR, three dimensional quantitative structure–activity relationship; CoMSIA, comparative molecular similarity index analysis.
© Copyright Policy
Related In: Results  -  Collection

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

f3-dddt-8-609: 3D-QSAR analyses.Notes: Structure alignment of the 61 molecules (left panel). CoMSIA contribution volumes from all molecules (right panel); volumes were plotted with 80 for positive contributions (green for steric and blue for electrostatic fields) and 20 for negative contributions (yellow for steric and red for electrostatic fields); the structure of compound 7 is represented.Abbreviations: 3D-QSAR, three dimensional quantitative structure–activity relationship; CoMSIA, comparative molecular similarity index analysis.
Mentions: A three dimensional quantitative structure–activity relationship molecular model was constructed after structures alignment from the IC50 values of all compounds, as shown on Figure 3. The positive contribution of quinoxaline at B-ring position (as observed in Table 1) appears to be related to electrostatic interactions of the two nitrogen heteroatoms (blue volumes). The better contribution of 1-naphthyl over 2-naphthyl (as observed in Table 2) might correlate both steric negative effects on the right edge of the site (yellow volume) and electrostatic negative effects on the top (red volume). Concerning methoxy contributions (as observed in Tables 1 and 2), the positive effects appear to be related to steric effects (green volume) at position 2′ and to both steric and electrostatic (blue volume) contributions at positions 4′ and 5′, whereas the negative contribution observed in some cases at position 3′ (such as in 12) as well as negative effects of hydroxyl at position 4′ (in 6 and 10) might be due to electrostatic antagonism (red volume). Other electrostatic negative effects related to B-ring positions 2 and 3 (red volume) appear to correlate the low efficiency of compounds containing hydrophilic substituents such as NO2 (in 37), Cl (in 43, 44, 51, and 58), Br (in 45 and 57), or CF3 (in 40, 42, or 54).

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