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

Ricardo J. Ferreira; Rafael Baptista; Alexis Moreno; Patricia G. Madeira; Ruttiros Khonkarn; Hélène Baubichon-Cortay; Daniel Jva Dos Santos; Pierre Falson; Maria José U. Ferreira

doi:10.4155/fmc-2017-0228

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

Ricardo J. Ferreira, Rafael Baptista, Alexis Moreno, Patricia G. Madeira, Ruttiros Khonkarn, Hélène Baubichon-Cortay, Daniel Jva Dos Santos, Pierre Falson, Maria José U. Ferreira

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	725-741
Number of pages	17
Journal	Future Medicinal Chemistry
Volume	10
Issue number	7
DOIs	https://doi.org/10.4155/fmc-2017-0228
Publication status	Published - Apr 2018
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2018 Newlands Press.

Funding

This project received funding from European Structural & Investment Funds through the COMPETE Programme and from National Funds through FCT – Fundac¸ão para a Ciência e a Tecnologia (FCT) under the Programme grants PTDC/QEQ-MED/0905/2012, UID/DTP/04138/2013 and SAICTPAC/0019/2015. RJ Ferreira acknowledges the PhD grant from FCT, SFRH/BD/84285/2012. 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. No writing assistance was utilized in the production of this manuscript.

Funders	Funder number
Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção	PTDC/QEQ-MED/0905/2012, SFRH/BD/84285/2012, UID/DTP/04138/2013, SAICTPAC/0019/2015
Fundació Catalana de Trasplantament
Programa Operacional Temático Factores de Competitividade

Keywords

ABC transporters
BCRP
MRP1
P-gp
flavanone
hydrazides
hydrazones
molecular docking
multidrug resistance
pharmacophore

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.4155/fmc-2017-0228

Cite this

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title = "Optimizing the flavanone core toward new selective nitrogen-containing modulators of ABC transporters",

abstract = "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.",

keywords = "ABC transporters, BCRP, MRP1, P-gp, flavanone, hydrazides, hydrazones, molecular docking, multidrug resistance, pharmacophore",

author = "Ferreira, {Ricardo J.} and Rafael Baptista and Alexis Moreno and Madeira, {Patricia G.} and Ruttiros Khonkarn and H{\'e}l{\`e}ne Baubichon-Cortay and {Dos Santos}, {Daniel Jva} and Pierre Falson and Ferreira, {Maria Jos{\'e} U.}",

note = "Publisher Copyright: {\textcopyright} 2018 Newlands Press.",

year = "2018",

month = apr,

doi = "10.4155/fmc-2017-0228",

language = "English",

volume = "10",

pages = "725--741",

journal = "Future Medicinal Chemistry",

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T1 - Optimizing the flavanone core toward new selective nitrogen-containing modulators of ABC transporters

AU - Ferreira, Ricardo J.

AU - Baptista, Rafael

AU - Moreno, Alexis

AU - Madeira, Patricia G.

AU - Khonkarn, Ruttiros

AU - Baubichon-Cortay, Hélène

AU - Dos Santos, Daniel Jva

AU - Falson, Pierre

AU - Ferreira, Maria José U.

PY - 2018/4

Y1 - 2018/4

N2 - 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.

AB - 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.

KW - ABC transporters

KW - BCRP

KW - MRP1

KW - P-gp

KW - flavanone

KW - hydrazides

KW - hydrazones

KW - molecular docking

KW - multidrug resistance

KW - pharmacophore

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JO - Future Medicinal Chemistry

JF - Future Medicinal Chemistry

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ER -

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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