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. In our previous work we determined the preferred position of the linker on the A-ring to be ortho, and found several substitution patterns at the additional ring that improved potency. In this study we investigated whether a methoxy group that improved the inhibitory activity of chalcones would also be beneficial for the acryloylphenylcarboxamide scaffold. Indeed, this modification led to highly potent ABCG2 inhibitors. To support the hypothesis of a beneficial effect of the amide linker, six acryloylphenylcarboxylates were synthesized and investigated for their inhibitory activity. Replacement of the amide linker with an ester group resulted in decreased inhibition. Molecular modeling showed that the conformational preference of both series differs, thereby explaining the positive effect of the amide linker. Several compounds were characterized in detail by investigating their intrinsic cytotoxicity and capacity to reverse MDR in MTT assays and their effect on vanadate-sensitive ATPase activity.

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 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.

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. In this series only methoxy groups were used as substituents as these had been proven superior for inhibitory activity of chalcones. All compounds were tested for their inhibitory activity, specificity and cytotoxicity. The most potent ABCG2 inhibitor in this series showed an IC50 value of 0.19 µM. It possesses low cytotoxicity (GI50 = 93 µM), the ability to reverse MDR and is nearly selective toward ABCG2. Most compounds containing dimethoxy groups showed slight activity against ABCB1 too. Among these three compounds (17, 19 and 24) showed even higher activity toward ABCB1 than ABCG2. All inhibitors were further screened for their effect on basal ATPase activity. Although the basal ATPase activity was partially stimulated, the compounds were not transported by ABCG2. Thus, quinazoline-chalcones are a new class of effective ABCG2 inhibitors.