New structure–activity relationships of chalcone inhibitors of breast cancer resistance protein: polyspecificity toward inhibition and critical substitutions against cytotoxicity

Abstract

Adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2) plays a major role in cancer cell multidrug resistance, which contributes to low efficacy of chemotherapy. Chalcones were recently found to be potent and specific inhibitors, but unfortunately display a significant cytotoxicity. A cellular screening against ABCG2-mediated mitoxantrone efflux was performed here by flow cytometry on 54 chalcone derivatives from three different series with a wide panel of substituents. The identified leads, with submicromolar IC 50 (half maximal inhibitory concentration) values, showed that the previously identified 2′-OH-4′,6′-dimethoxyphenyl, as A-ring, could be efficiently replaced by a 2′-naphthyl group, or a 3′,4′-methylenedioxyphenyl with lower affinity. Such a structural variability indicates polyspecificity of the multidrug transporter for inhibitors. At least two methoxyl groups were necessary on B-ring for optimal inhibition, but substitution at positions 3, 4, and 5 induced cytotoxicity. The presence of a large O-benzyl substituent at position 4 and a 2′-naphthyl as A-ring markedly decreased the cytotoxicity, giving a high therapeutic ratio, which constitutes a critical requirement for future in-vivo assays in animal models.

Mechanism of inhibition of α-glucosidase activity by bavachalcone

“…Psoralea corylifolia is the dried fruit of the legume Psoralea corylifolia L. Many studies have shown that it contains a variety of active components, such as monoterpenols, monoterpenol dimers, flavonoids, chalcone, coumarins, isoflavones, and fatty acids (Hollander, 1992). It displays anti-inflammatory, cardiovascular protective, and hypoglycemic properties, and good pharmacological activity (Corrêa et al, 2008;Xu et al, 2019;Pietro et al, 2013). Bavachalcone is a chalcone compound with a 1,3-diphenylpropenone skeleton (Figure 1) isolated from the traditional Chinese medicine Fructus Psoraleae.…”

Marine Natural Products as Breast Cancer Resistance Protein Inhibitors

“…From all evaluated substituents, 2′-naphthyl and 3′, 4′ methylene-dioxy-phenyl were the most effective ( Figure 2 ). Also, the substitution at position 4 of ring B is critical; in this position an O -benzyl residue is the most effective substituent for the inhibition and cytotoxicity [ 38 ]. Many other studies have demonstrated that chalcones are promising selective BCRP inhibitors [ 4 , 39 , 40 , 41 ], such as Compounds 1 and 2 ( Figure 3 ), which have now become good candidates for preclinical experiments [ 4 ].…”