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

Abstract

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.

• Authors: Imen Dakhlaoui, Sahel Vahdati, Emna Maalej, Fakher Chabchoub, Michael Wiese, Jose Marco-Contelles, Lhassane Ismaili
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 116 Pg. 105326 (11 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 34536930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Antineoplastic Agents
• Neoplasm Proteins
• Pyrimidines

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2 (antagonists & inhibitors, metabolism)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Female
• Humans
• Molecular Structure
• Neoplasm Proteins (antagonists & inhibitors, metabolism)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured