Synthesis and biological assessment of new pyrimidopyrimidines as inhibitors of breast cancer resistance protein (ABCG2)

[Display omitted] •Pyrimidopyrimidines: new Inhibitors of Breast Cancer Resistance Protein.•7 g, 7 h and 7i are the most potent inhibitors of ABCG2 with IC50 equal to 0.487, 0.493 and 0.434 μM respectively.•7 g and 7i showed additional inhibition of ABCB1 with IC50 equal to 5.46 and 7.88 μM.•No inhibition of ABCB1 and ABCC1 was observed for 7 h.•7 h is the most promising agent investigated here with full selectivity and effective inhibition of ABCG2. Multidrug resistance constitutes a serious obstacle of the treatment success of cancer by chemotherapy. Mostly it is driven by expression of ABC transport proteins that actively efflux the anticancer agents out of the cell. This work describes the design and synthesis of 12 new pyrimidopyrimidines, as well as their inhibition of ABCG2 a transporter referred also to as breast cancer resistance protein, the selectivity versus ABCB1 (P-glycoprotein/P-gp) and ABCC1 as well as the investigation of their accumulation in single cells. From these results, N-(3,5-dimethoxyphenyl)-2-methyl-7-phenyl-5-(p-tolyl)pyrimido[4,5-d]pyrimidin-4-amine 7 h was identified as promising hit that deserves further investigation showing a selective and effective inhibition of ABCG2 with IC50 equal to 0.493 µM only 2-fold less active than Ko143.