Symmetric bis-chalcones as a new type of breast cancer resistance protein inhibitors with a mechanism different from that of chromones

Evelyn Winter; Patrícia Devantier Neuenfeldt; Louise Domeneghini Chiaradia-Delatorre; Charlotte Gauthier; Rosendo Augusto Yunes; Ricardo José Nunes; Tânia Beatriz Creczynski-Pasa; Attilio Di Pietro

doi:10.1021/jm401879z

Symmetric bis-chalcones as a new type of breast cancer resistance protein inhibitors with a mechanism different from that of chromones

J Med Chem. 2014 Apr 10;57(7):2930-41. doi: 10.1021/jm401879z. Epub 2014 Mar 24.

Authors

Evelyn Winter¹, Patrícia Devantier Neuenfeldt, Louise Domeneghini Chiaradia-Delatorre, Charlotte Gauthier, Rosendo Augusto Yunes, Ricardo José Nunes, Tânia Beatriz Creczynski-Pasa, Attilio Di Pietro

Affiliation

¹ Equipe Labellisée Ligue 2014, BMSSI UMR5086 CNRS/Université Lyon 1, IBCP, 69367 Lyon, France.

PMID: 24611893
DOI: 10.1021/jm401879z

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / antagonists & inhibitors*
ATP-Binding Cassette Transporters / metabolism
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Biological Transport / drug effects
Cell Proliferation / drug effects*
Cells, Cultured
Chalcones / chemistry
Chalcones / pharmacology*
Chromones / chemistry
Chromones / pharmacology*
Drug Resistance, Multiple / drug effects
Drug Resistance, Neoplasm / drug effects
Drug Synergism
HEK293 Cells
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / pathology
Mitoxantrone / pharmacology
Molecular Structure
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / metabolism
Pancreatic Neoplasms / drug therapy
Pancreatic Neoplasms / pathology
Structure-Activity Relationship

Substances

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Antineoplastic Agents
Chalcones
Chromones
Neoplasm Proteins
Mitoxantrone