Structure-activity relationships of chromone derivatives toward the mechanism of interaction with and inhibition of breast cancer resistance protein ABCG2

Evelyn Winter, Florine Lecerf-Schmidt, Gustavo Gozzi, Basile Peres, Mark Lightbody, Charlotte Gauthier, Csilla Ozvegy-Laczka, Gergely Szakacs, Balazs Sarkadi, Taînia B. Creczynski-Pasa, Ahcène Boumendjel, Attilio Di Pietro

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

We recently identified a chromone derivative, 5-(4-bromobenzyloxy)-2-(2-(5- methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one, named here as chromone 1, as a potent, selective, nontoxic, and nontransported inhibitor of ABCG2-mediated drug efflux (Valdameri et al. J. Med. Chem. 2012, 55, 966). We have now synthesized a series of 14 derivatives to study the structure-activity relationships controlling both drug efflux and ATPase activity of ABCG2 and to elucidate their molecular mechanism of interaction and inhibition. It was found that the 4-bromobenzyloxy substituent at position 5 and the methoxyindole are important for both inhibition of mitoxantrone efflux and inhibition of basal ATPase activity. Quite interestingly, methylation of the central amide nitrogen strongly altered the high affinity for ABCG2 and the complete inhibition of mitoxantrone efflux and coupled ATPase activity. These results allowed the identification of a critical central inhibitory moiety of chromones that has never been investigated previously in any series of inhibitors.

Original languageEnglish
Pages (from-to)9849-9860
Number of pages12
JournalJournal of Medicinal Chemistry
Volume56
Issue number24
DOIs
Publication statusPublished - Dec 27 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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