Details

Autor(en) / Beteiligte

• Kraege, Stefanie
• Stefan, Katja
• Juvale, Kapil
• Ross, Thomas
• Willmes, Thomas
• Wiese, Michael

Titel

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

Ist Teil von

• European journal of medicinal chemistry, 2016-07, Vol.117, p.212-229

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Combination of quinazoline and chalcone scaffolds to heterodimeric inhibitors.•Quinazoline-chalcones are potent inhibitors of ABCG2.•Most potent compound was found to be selective, non-toxic and able to reverse MDR.•Stimulate ATPase activity without being transported.•Three compounds show dual inhibitory behavior.