Chromones bearing amino acid residues: Easily accessible and potent inhibitors of the breast cancer resistance protein ABCG2

• Published in: European journal of medicinal chemistry 2020-09, Vol.202 (C), p.112503, Article 112503
• Main Authors: Roussel, Emile, Moréno, Alexis, Altounian, Nicolas, Philouze, Christian, Pérès, Basile, Thomas, Aline, Renaudet, Olivier, Falson, Pierre, Boumendjel, Ahcène
• Format: Article
• Language: English
• Subjects: ABCG2; Amino Acids - chemistry; Amino Acids - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily G, Member 2 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; BCRP; Cancer; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Chemical Sciences; Chromones; Chromones - chemical synthesis; Chromones - chemistry; Chromones - pharmacology; Dose-Response Relationship, Drug; Drug efflux; Drug Screening Assays, Antitumor; Humans; Inhibitors; Life Sciences; MDR; Medicinal Chemistry; Mice; Molecular Docking Simulation; Molecular Structure; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112503

The Breast Cancer Resistance Protein (BCRP/ABCG2) belongs to the G class of ABC (ATP-Binding Cassette) proteins, which is known as one of the main transporters involved in the multidrug resistance (MDR) phenotype that confer resistance to anticancer drugs. The aim of this study was to design, synthesize and develop new potent and selective inhibitors of BCRP that can be used to abolish MDR and potentialize clinically used anticancer agents. In previous reports, we showed the importance of chromone scaffold and hydrophobicity for the inhibition of ABC transporters. In the present study we report the design and development of chromones linked to one or two amino acids residues that are either hydrophobic or found in the structure of FTC, one of most potent (but highly toxic) inhibitors of BCRP. Herewith, we report the synthesis and evaluation of 13 compounds. The studied molecules were found to be not toxic and showed strong inhibition activity as well as high selectivity toward BCRP. The highest activity was obtained with the chromone bearing a valine residue (9c) which showed an inhibition activity against BCRP of 50 nM. The rationalization of the inhibition potential of the most active derivatives was performed through docking studies. Taken together, the ease of synthesis and the biological profile of these compounds render them as promising candidates for further development in the field of anticancer therapy. [Display omitted] •Chromones linked to amino acids were designed and synthesized in multigram scale.•Chromones bearing amino acids inhibit the human BCRP/ABCG2 transporter.•The most active compounds inhibit BCRP at nanomolar range with high selectivity.•Chromones bearing amino acids can be considered for use in chemotherapy in order to enhance clinically used anticancer drugs.