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Acryloylphenylcarboxamides: A New Class of Breast Cancer Resistance Protein (ABCG2) Modulators
Author(s) -
Kraege Stefanie,
Köhler Sebastian C.,
Wiese Michael
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600341
Subject(s) - abcg2 , chalcone , moiety , linker , multiple drug resistance , chemistry , transporter , cytotoxicity , abcc1 , stereochemistry , structure–activity relationship , atp binding cassette transporter , combinatorial chemistry , biochemistry , in vitro , gene , antibiotics , computer science , operating system
Chalcones are easily synthesized natural precursors of secondary plant metabolites, and their derivatives show various biological activities including inhibition of ABC transporters. Especially, their role as inhibitors of ABCG2, the most recently discovered ABC transporter involved in multidrug resistance, inspired the synthesis of new structurally diverse derivatives. Therefore, we combined the typical chalcone moiety with several acid chlorides by using an amide linker at position 2′, 3′, or 4′ on ring A of the chalcone. The resulting 35 compounds covered a wide spectrum of substitution patterns, which allowed development of structure–activity relationships and to find the optimal structural features for further investigations. Synthesized acryloylphenylcarboxamides were investigated for their inhibitory activity against ABCG2 and their behavior toward ABCB1 and ABCC1. Furthermore, for the most promising compounds, their intrinsic cytotoxicity and their ability to reverse ABCG2‐mediated multidrug resistance were determined.