Substituted chromones as highly potent nontoxic inhibitors, specific for the breast cancer resistance protein.

Abstract

A series of 13 disubstituted chromones was synthesized. Two types of substituents, on each side of the scaffold, contributed to both the potency of ABCG2 inhibition and the cytotoxicity. The best compound, 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one (6g), displayed high-affinity inhibition and low cytotoxicity, giving a markedly high therapeutic index. The chromone derivative specifically inhibited ABCG2 versus other multidrug ABC transporters and was not transported. It constitutes a highly promising candidate for in vivo chemosensitization of ABCG2-expressing tumors.

• Authors: Glaucio Valdameri, Estelle Genoux-Bastide, Basile Peres, Charlotte Gauthier, Jérôme Guitton, Raphaël Terreux, Sheila M B Winnischofer, Maria E M Rocha, Ahcène Boumendjel, Attilio Di Pietro
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 2 Pg. 966-70 (Jan 26 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22165858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Chromones
• Indoles
• Neoplasm Proteins
• Mitoxantrone

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (antagonists & inhibitors, genetics, metabolism)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Biological Transport (drug effects)
• Cell Proliferation (drug effects)
• Chromones (chemical synthesis, chemistry, pharmacology)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• HEK293 Cells
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Mitoxantrone (pharmacology)
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Structure-Activity Relationship
• Transfection