https://orcid.org/0000-0001-7936-9326
Abstract
Aim: BCRP plays a major role in the efflux of cytotoxic molecules, limiting their antiproliferative activity. We aimed to design and synthesize new BCRP inhibitors to render cancerous tumors more sensitive toward anticancer agents. Materials & methods: Based on our previous work, we conceived potential BCRP inhibitors derived from 1,3,4-oxadiazoles bearing two substituted phenyl rings. Results: Evaluating 19 derivatives, we found that 2,5-diaryl-1,3,4-oxadiazoles possessing methoxy groups were the most active. The highest activity was recorded with derivatives bearing three methoxy groups. The most active compound (3j) was selective in inhibiting BCRP and nontoxic as evidenced by cellular tests. Conclusion: 3j is a promising BCRP inhibitor thanks to its synthetic accessibility and biological profile.
Substituted oxadiazoles were investigated as inhibitors of BCRP.
The most active inhibitors can be synthesized in one step with acceptable yields.
The most active compound (3j) strongly inhibited BCRP (ABCG2) with no toxicity even at high concentrations.
3j is specific to BCRP compared with P-gp and MRP1.
3j showed higher solubility in water than the most potent inhibitors reported so far.
Author contributions
W Yi performed the synthesis and characterization of the compounds disclosed in the study. V-K Tran-Nguyen performed the docking study and contributed to manuscript writing. A Boumendjel supervised and coordinated the study. He wrote the first draft of the manuscript.
Financial disclosure
A Boumendjel is thankful to the Chemisty Biology and Health Graduate School (CBH-GS) (ANR-17-EURE-0003) for financial support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.
Acknowledgments
The authors are very thankful to A Di Pietro (Centre National de la Recherche Scientifique, Lyon, France) for the biological assays on BCRP.