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

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.

Keywords:

• ABC transporters
• breast cancer resistance protein (BCRP)/ABCG2
• quinoxaline derivatives
• structure–activity relationships
• drug efflux

Acknowledgments

EW and GJG were recipients of mobility doctoral fellowships from the Brazilian CAPES (Process number 8792127) and CNPq-CAPES (Science Without Borders Program 245762/2012-4), respectively. NDY is a recipient of a postdoctoral fellowship for the Control of Cancer-CNPq (Science without Borders Program) and CG is the recipient of a doctoral fellowship from the Ligue Nationale Contre le Cancer. Financial support was provided in France by the CNRS and Université Lyon 1 (UMR 5086), the Ligue Nationale Contre le Cancer (Equipe labellisée Ligue 2013), an international grant from French ANR and Hungarian NIH (2010-INT-1101-01), and in Brazil by the CNPq. We acknowledge the Chemistry Department and the Molecular Structural Biology Center from the Federal University of Santa Catarina, Brazil, for the respective NMR and micrOTOF-QII equipment used in the chemical analyses. We also thank PD Neuenfeldt for performing the NMR analyses.

Disclosure

The authors report no conflicts of interest in this work.