Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp

Abstract P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracell...

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Autores principales:	Jerónimo Laiolo, Priscila Ailin Lanza, Oscar Parravicini, Cecilia Barbieri, Daniel Insuasty, Justo Cobo, D. Mariano Adolfo Vera, Ricardo Daniel Enriz, Maria Cecilia Carpinella
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/98b225c1e09c43bfa1d0517e683523c4
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spelling	oai:doaj.org-article:98b225c1e09c43bfa1d0517e683523c42021-12-02T17:08:23ZStructure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp10.1038/s41598-021-96226-62045-2322https://doaj.org/article/98b225c1e09c43bfa1d0517e683523c42021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96226-6https://doaj.org/toc/2045-2322Abstract P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure–activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.Jerónimo LaioloPriscila Ailin LanzaOscar ParraviciniCecilia BarbieriDaniel InsuastyJusto CoboD. Mariano Adolfo VeraRicardo Daniel EnrizMaria Cecilia CarpinellaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jerónimo Laiolo Priscila Ailin Lanza Oscar Parravicini Cecilia Barbieri Daniel Insuasty Justo Cobo D. Mariano Adolfo Vera Ricardo Daniel Enriz Maria Cecilia Carpinella Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp
description	Abstract P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure–activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.
format	article
author	Jerónimo Laiolo Priscila Ailin Lanza Oscar Parravicini Cecilia Barbieri Daniel Insuasty Justo Cobo D. Mariano Adolfo Vera Ricardo Daniel Enriz Maria Cecilia Carpinella
author_facet	Jerónimo Laiolo Priscila Ailin Lanza Oscar Parravicini Cecilia Barbieri Daniel Insuasty Justo Cobo D. Mariano Adolfo Vera Ricardo Daniel Enriz Maria Cecilia Carpinella
author_sort	Jerónimo Laiolo
title	Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp
title_short	Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp
title_full	Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp
title_fullStr	Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp
title_full_unstemmed	Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp
title_sort	structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by p-gp
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/98b225c1e09c43bfa1d0517e683523c4
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Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp

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