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.

New Chalcone Derivative Inhibits ABCB1 in Multidrug Resistant T-cell Lymphoma and Colon Adenocarcinoma Cells

“…In line with our findings, there are several additional studies reporting the ability of chalcones to bind to ABCB1 and inhibit its transport activity (12,31). Multidrug resistance reversal activity of chalcones, including inhibition of other membrane transporters, has been previously demonstrated for example in human breast cancer (15,32,33) or human glioblastoma cells (13). Herein, the tested chalcone 1C was even more potent inhibitor of ABCB1 than verapamil.…”

Clinically-Relevant ABC Transporter for Anti-Cancer Drug Resistance

“…As mentioned earlier, introducing different groups on the chalcone template can produce corresponding inhibitory effects on P-gp and BCRP. With respect to chalcone derivatives, the replacement of B-ring with a quinoxaline moiety accompanied with different patterns of hydroxy and methoxy substitutions at A-ring can result in higher and obvious BCRP inhibitory effects in HEK293-ABCG2 cells (Winter et al, 2014). The quinoxaline contributes the electrostatic interactions between the two nitrogen atoms and the ABCG2 protein (Kraege et al, 2016b).…”

Design, Synthesis, In silico and In Vitro Anticancer Activity of Novel Bis‐Furanyl‐Chalcone Derivatives Linked through Alkyl Spacers

“…These types of compounds that can be obtained directly by aldol reactions under basic conditions are considered as key precursors for flavonoid and isoflavonoid syntheses. [1][2][3][4][5][6][7][8] Different studies showed that chalcone compounds display a wide extend of biological activities including medicinal and pharmacological activities, such as antioxidant, antiviral, cytotoxic, antitubercular, anti-inflammatory, antimalarial, anticancer, antimicrobial, and antileishmanial. [7,[9][10][11] Chalcones, in particular, display varying levels of inhibition during the proliferative processes in different cancer cell lines.…”

“…Chalcones, structurally, are 1,3‐diaryl‐2‐propen‐1‐ones in which a two aromatic rings (ring A and ring B, Figure 1), are joined by a three‐carbon α , β ‐unsaturated carbonyl system as depicted in Figure 1. These types of compounds that can be obtained directly by aldol reactions under basic conditions are considered as key precursors for flavonoid and isoflavonoid syntheses [1–8] …”