Optimization of Acryloylphenylcarboxamides as Inhibitors of ABCG2 and Comparison with Acryloylphenylcarboxylates.

ABCG2 belongs to the superfamily of ATP binding cassette (ABC) proteins and is associated with the limited success of anticancer chemotherapy, given its responsibility for the cross-resistance of tumor cells, known as multidrug resistance (MDR). Several classes of ABCG2 inhibitors were developed for increasing the efficacy of chemotherapy. A series of chalcones coupled to an additional aromatic residue was synthesized and investigated for their inhibition of ABC transporters.

Acryloylphenylcarboxamides: A New Class of Breast Cancer Resistance Protein (ABCG2) Modulators.

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 combination of quinazoline and chalcone moieties leads to novel potent heterodimeric modulators of breast cancer resistance protein (BCRP/ABCG2).

During the last decade it has been found that chalcones and quinazolines are promising inhibitors of ABCG2. The combination of these two scaffolds offers a new class of heterocyclic compounds with potentially high inhibitory activity against ABCG2. For this purpose we investigated 22 different heterodimeric derivatives.