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

被引：17

作者：

Dakhlaoui, Imen ^{[1
,2
]}

Vahdati, Sahel ^{[3
]}

Maalej, Emna ^{[1
,4
]}

Chabchoub, Fakher ^{[1
]}

Wiese, Michael ^{[3
]}

Marco-Contelles, Jose ^{[5
]}

Ismaili, Lhassane ^{[2
]}

机构：

[1] Univ Sfax, Fac Sci Sfax, Lab Chim Appl Heterocycles Corps Gras & Polymeres, BP 802, Sfax 3000, Tunisia

[2] Univ Bourgogne Franche Comte, Lab Chim Organ & Therapeut Neurosci Integrat & Cl, UFR Sante, 19 Rue Ambroise Pare, F-25000 Besancon, France

[3] Univ Bonn, Pharmaceut Inst, Immenburg 4, D-53121 Bonn, Germany

[4] Inst Natl Rech & Anal Physicochim Technopole, Lab Mat Traitement & Anal LMTA, Ariana, Tunisia

[5] CSIC, Lab Med Chem IQOG, Juan de la Cierva 3, Madrid 28006, Spain

来源：

BIOORGANIC CHEMISTRY | 2021年 / 116卷

关键词：

ABC transporter; ABCG2; inhibitor; ABCB1; ABCC1; Multidrug resistance; Pyrimidopyrimidines; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; MOLECULAR-MECHANISMS; BINDING; TRANSPORTERS; POTENT; MODULATORS; FAMILY;

D O I：

10.1016/j.bioorg.2021.105326

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 mu M only 2-fold less active than Ko143.

引用

页数：10

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