Symmetric Bis-chalcones as a New Type of Breast Cancer Resistance Protein Inhibitors with a Mechanism Different from That of Chromones

Abstract

Potent ABCG2 inhibitors were recently identified as asymmetric chromones with different types of substituents. We here synthesized symmetric bis-chalcones that were differently substituted and screened for their ability to inhibit mitoxantrone efflux from ABCG2-transfected HEK293 cells. Potent bis-chalcone inhibitors were identified, the efficiency depending on both position of the central ketone groups and the number and positions of lateral methoxy substituents. The best derivative, namely, 1p, was selective for ABCG2 over P-glycoprotein and MRP1, appeared not to be transported by ABCG2, and was at least as active on various drug-selected cancer cells overexpressing ABCG2. Compound 1p stimulated the ABCG2 basal ATPase activity by contrast to a chromone lead that inhibited it, suggesting different mechanisms of interaction. Combination of both types of inhibitors produced synergistic effects, leading to complete inhibition at very low concentrations.

A Way to Improve Luminescent Efficiency of Bis-Chalcone Derivatives

“…This work provides another way to improve the emission efficiency of chalcone related compounds apart from using the complexation method as reported by D' Aléo et al (2012). Compounds 1a and 1b were reported by a number of researchers; however, the compounds were mainly used as a starting material for other compounds' synthesis and also were studied concerning their biological activities [18][19][20][21][22][23][24][25], yet, the photophysical properties of 1a and 1b were not the main concern in these papers.…”

Phenolic indeno[1,2-b]indoles as ABCG2-selective potent and non-toxic inhibitors stimulating basal ATPase activity

“…12 Synthetic derivatives were developed, resulting in the highly potent Ko143 inhibitor, which however still retained significant residual toxicity. 13 Screening of different classes of flavonoids identified interesting inhibitors such as hydrophobic flavones, acridones, chromones, asymmetric chalcones, and symmetric bis -chalcones, 14 some of them being active in vivo in mouse models. 15 , 16 …”

Diverse Molecular Targets for Chalcones with Varied Bioactivities

“…Rangel et al [ 169 ] screened fifty-four synthetic chalcones for BCRP inhibition by monitoring cellular mitoxantrone accumulation, and one of the most potent compounds 93 was non-cytotoxic itself but able to sensitize resistant cells to mitoxantrone to a level comparable to the sensitive cells. Similarly, Winter et al [ 170 ] constructed a library of symmetric bis-chalcones and tested their BCRP inhibitory activity with the same method, where activity from zero to complete inhibition was observed with 5 μM of chalcones, demonstrating a sharp SAR relationship. The most potent compound 94 completely sensitized resistant cells to mitoxantrone at sub-micromolar concentration.…”