Design and synthesis of new potent N,N-bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents

© 2018 Elsevier Masson SAS A series of 1,4-substituted arylalkyl piperazine derivatives were synthesized and studied with the aim to obtain potent P-gp-dependent multidrug-resistant (MDR) reversers. The new compounds were designed on the basis of the structures of our previous arylamine ester deriva...

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Main Authors: Silvia Dei, Marcella Coronnello, Gianluca Bartolucci, Dina Manetti, Maria Novella Romanelli, Chatchanok Udomtanakunchai, Milena Salerno, Elisabetta Teodori
Format: Journal
Published: 2018
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http://cmuir.cmu.ac.th/jspui/handle/6653943832/48477
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spelling th-cmuir.6653943832-484772018-04-25T10:12:52Z Design and synthesis of new potent N,N-bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents Silvia Dei Marcella Coronnello Gianluca Bartolucci Dina Manetti Maria Novella Romanelli Chatchanok Udomtanakunchai Milena Salerno Elisabetta Teodori © 2018 Elsevier Masson SAS A series of 1,4-substituted arylalkyl piperazine derivatives were synthesized and studied with the aim to obtain potent P-gp-dependent multidrug-resistant (MDR) reversers. The new compounds were designed on the basis of the structures of our previous arylamine ester derivatives endowed with high P-gp-dependent multidrug resistance reversing activity. All new compounds were active in the pirarubicin uptake assay on the doxorubicin–resistant erythroleukemia K562 cells (K562/DOX). In particular, compounds bearing methoxy aromatic moieties showed fairly high reversal activities. The most potent compounds, 8, 9, 10 and 13, were further studied by evaluating their doxorubicin cytotoxicity enhancement (reversal fold, RF) and the inhibition of P-gp-mediated rhodamine-123 (Rhd 123) efflux on the K562/DOX cell line. The results of all pharmacological assays indicated that the combination of a basic piperazine scaffold with arylalkyl residues allowed us to obtain very interesting P-gp modulating compounds. Two long-lasting P-gp pump modulators (9 and 10) were identified; they were able to inhibit remarkably the P-gp substrate rhodamine-123 efflux on the resistant K562/DOX cell line after 60 min. Overall compound 9 appeared the most promising compound being a potent and long-lasting P-gp–dependent MDR modulator. 2018-04-25T10:12:52Z 2018-04-25T10:12:52Z 2018-03-10 Journal 17683254 02235234 2-s2.0-85041407631 10.1016/j.ejmech.2018.01.092 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85041407631&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/48477
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
description © 2018 Elsevier Masson SAS A series of 1,4-substituted arylalkyl piperazine derivatives were synthesized and studied with the aim to obtain potent P-gp-dependent multidrug-resistant (MDR) reversers. The new compounds were designed on the basis of the structures of our previous arylamine ester derivatives endowed with high P-gp-dependent multidrug resistance reversing activity. All new compounds were active in the pirarubicin uptake assay on the doxorubicin–resistant erythroleukemia K562 cells (K562/DOX). In particular, compounds bearing methoxy aromatic moieties showed fairly high reversal activities. The most potent compounds, 8, 9, 10 and 13, were further studied by evaluating their doxorubicin cytotoxicity enhancement (reversal fold, RF) and the inhibition of P-gp-mediated rhodamine-123 (Rhd 123) efflux on the K562/DOX cell line. The results of all pharmacological assays indicated that the combination of a basic piperazine scaffold with arylalkyl residues allowed us to obtain very interesting P-gp modulating compounds. Two long-lasting P-gp pump modulators (9 and 10) were identified; they were able to inhibit remarkably the P-gp substrate rhodamine-123 efflux on the resistant K562/DOX cell line after 60 min. Overall compound 9 appeared the most promising compound being a potent and long-lasting P-gp–dependent MDR modulator.
format Journal
author Silvia Dei
Marcella Coronnello
Gianluca Bartolucci
Dina Manetti
Maria Novella Romanelli
Chatchanok Udomtanakunchai
Milena Salerno
Elisabetta Teodori
spellingShingle Silvia Dei
Marcella Coronnello
Gianluca Bartolucci
Dina Manetti
Maria Novella Romanelli
Chatchanok Udomtanakunchai
Milena Salerno
Elisabetta Teodori
Design and synthesis of new potent N,N-bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents
author_facet Silvia Dei
Marcella Coronnello
Gianluca Bartolucci
Dina Manetti
Maria Novella Romanelli
Chatchanok Udomtanakunchai
Milena Salerno
Elisabetta Teodori
author_sort Silvia Dei
title Design and synthesis of new potent N,N-bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents
title_short Design and synthesis of new potent N,N-bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents
title_full Design and synthesis of new potent N,N-bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents
title_fullStr Design and synthesis of new potent N,N-bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents
title_full_unstemmed Design and synthesis of new potent N,N-bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents
title_sort design and synthesis of new potent n,n-bis(arylalkyl)piperazine derivatives as multidrug resistance (mdr) reversing agents
publishDate 2018
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85041407631&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/48477
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