Optimizing the flavanone core toward new selective nitrogen-containing modulators of ABC transporters

Aim: Naringenin (1), isolated in large amount from the aerial parts of Euphorbia pedroi, was chemically derivatized to yield 18 imine derivatives (2–19) and three alkylated derivatives through a Mannich-type reaction (20–22) that were tested as multidrug resistance (MDR) reversers in cancer cells. Results/methodology: While hydrazone (2–4) and azine (5–13) derivatives showed an improvement in their MDR reversal activities against the breast cancer resistance protein, carbohydrazides 14-19 revealed an enhancement in MDR reversal activity toward the multidrug resistance protein 1. Conclusion: The observed activities, together with pharmacophoric analysis and molecular docking studies, identified the spatial orientation of the substituents as a key structural feature toward a possible mechanism by which naringenin derivatives may reverse MDR in cancer.

Ricardo J Ferreira 1, Rafael Baptista 1, Alexis Moreno 2, Patricia G Madeira 2, Ruttiros Khonkarn 2, Hélène Baubichon-Cortay 2, Daniel JVA dos Santos 1,3, Pierre Falson 2* and Maria-José U Ferreira 1*

1 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649–003 Lisboa, Portugal.

2 Drug Resistance & Membrane Protein team, Molecular Microbiology & Structural Biochemistry lab, Institut de Biologie et Chimie des Proteines (IBCP), Lyon, France.

3 LAQV@REQUIMTE, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre, 4169–007 Porto, Portugal.

http://doi.org/10.4155/fmc-2017-0228

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