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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

Structure of chalcones with a 3,4-methylenedioxy-phenyl or a 2-naphthyl group as A-ring, and methoxy substituents on the B-ring.Note: Compounds previously identified in Rangel et al.20Abbreviation: R, ring.
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f2-dddt-8-609: Structure of chalcones with a 3,4-methylenedioxy-phenyl or a 2-naphthyl group as A-ring, and methoxy substituents on the B-ring.Note: Compounds previously identified in Rangel et al.20Abbreviation: R, ring.

Mentions: Although the B-ring could accommodate bicyclic rings (accompanied by OCH3 substituents on the phenyl A-ring) as well as OCH3-substituted phenyl (with bicyclic rings instead of A-ring), the inhibitors were not equivalent in potency. Indeed, the compounds containing a 3′,4′-methylenedioxyphenyl unit as A-ring and methoxy substituents on B-ring were more, or much more, potent than the inverted compounds containing a 3,4-methylenedioxyphenyl unit at B-ring and methoxy substituents on the phenyl A-ring: in 38 versus 25 (12-fold increase), in 33 versus 31 or in D of Figure 2 versus 24 (10-fold increase), and in C of Figure 2 versus 23 or in A of Figure 2 versus 22 (5-to-6-fold increase); however, a slightly opposite effect was observed in 32 versus 26 (2-fold decrease). Moreover, the compounds containing a 2′-naphthyl unit as A-ring and methoxy substituents on phenyl B-ring were more efficient than the inverted compounds containing a 2-naphthyl unit as B-ring and methoxy substituents on phenyl A-ring: in 53 versus 14 (3-fold increase) as well as in G of Figure 2 versus 18 (11-fold increase).


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)

Structure of chalcones with a 3,4-methylenedioxy-phenyl or a 2-naphthyl group as A-ring, and methoxy substituents on the B-ring.Note: Compounds previously identified in Rangel et al.20Abbreviation: R, ring.
© Copyright Policy
Related In: Results  -  Collection

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

f2-dddt-8-609: Structure of chalcones with a 3,4-methylenedioxy-phenyl or a 2-naphthyl group as A-ring, and methoxy substituents on the B-ring.Note: Compounds previously identified in Rangel et al.20Abbreviation: R, ring.
Mentions: Although the B-ring could accommodate bicyclic rings (accompanied by OCH3 substituents on the phenyl A-ring) as well as OCH3-substituted phenyl (with bicyclic rings instead of A-ring), the inhibitors were not equivalent in potency. Indeed, the compounds containing a 3′,4′-methylenedioxyphenyl unit as A-ring and methoxy substituents on B-ring were more, or much more, potent than the inverted compounds containing a 3,4-methylenedioxyphenyl unit at B-ring and methoxy substituents on the phenyl A-ring: in 38 versus 25 (12-fold increase), in 33 versus 31 or in D of Figure 2 versus 24 (10-fold increase), and in C of Figure 2 versus 23 or in A of Figure 2 versus 22 (5-to-6-fold increase); however, a slightly opposite effect was observed in 32 versus 26 (2-fold decrease). Moreover, the compounds containing a 2′-naphthyl unit as A-ring and methoxy substituents on phenyl B-ring were more efficient than the inverted compounds containing a 2-naphthyl unit as B-ring and methoxy substituents on phenyl A-ring: in 53 versus 14 (3-fold increase) as well as in G of Figure 2 versus 18 (11-fold increase).

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