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.
Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Stefanie
S
Kraege
Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Katja
K
Stefan
Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Kapil
K
Juvale
Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Thomas
T
Ross
Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Thomas
T
Willmes
Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany. Electronic address: mwiese@uni-bonn.de.
Michael
M
Wiese
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000737:chemistry*; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D047188:Chalcones; D003603:Cytotoxins; D009363:Neoplasm Proteins; D011799:Quinazolines
ABC transporter; ABCG2; ATPase; Chalcones; Multidrug resistance; Pheophorbide A assay; Quinazoline-chalcones; Quinazolines