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Novel Quercetin-1,2,3- Triazole Hybrids using the 1,3-Dipolar Cycloaddition (Click) Reaction: synthesis and antiproliferative activity assays
1, 2, 3 , 4 , 1, 2 , 1, 2 , 5 , * 3
1  University of Évora, Department of Medical Sciences and Health. School of Health and Human Development
2  Institute of Earth Sciences - ICT, University of Évora
3  LAQV-REQUIMTE - Laboratório Associado para a Química Verde - Universidade de Évora , IIFA
4  University of Évora, Department of Chemistry and Biochemistry. School of Sciences and Technologies
5  University of Coimbra, Faculty of Pharmacy
Academic Editor: Alfredo Berzal-Herranz (registering DOI)

Quercetin is a polyphenolic flavonoid with recognized strong antioxidant potential, which can prevent and treat several diseases. Hybrids containing a heterocyclic 1,2,3-triazole have shown promising biological properties, such as anticancer, anti-Alzheimer’s, among others. The hybridization of these two entities can allow the discovery of new molecules with more potent biological properties.

Novel quercetin-1,2,3-triazole hybrids were prepared in good to excelent yields via Cu(I)-catalyzed azide-alkyne cycloaddition reaction under microwave irradiation. These new hybrids contain a 1,4-disubstituted 1,2,3-triazole ring at the 3-OH position of quercetin whilst the remaining hydroxyl groups were either protected as methyl or benzyl groups or left unprotected.

All the quercetin-1,2,3-triazole hybrids I–IV were tested on REM-134 canine mammary cancer cell line, which is commonly used as a translational model for human breast cancer. These new analogues exhibit potent antiproliferative activity against this cancer cell line. The results show that some of these new quercetin-1,2,3-triazole hybrids have better activity than quercetin itself. Our best inhibitors displayed IC50 values in the range of 41–180 nM, which will be a promising contribution for treatment of both canine and human breast cancer.

Keywords: quercetin, 1,2,3-triazole, hybrids, antitumor, antiproliferative, REM-134, breast cancer, canine