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

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

  • Eur J Med Chem. 2018 Mar 10;147:7-20. doi: 10.1016/j.ejmech.2018.01.092.
Silvia Dei 1 Marcella Coronnello 2 Gianluca Bartolucci 1 Dina Manetti 1 Maria Novella Romanelli 1 Chatchanok Udomtanakunchai 3 Milena Salerno 4 Elisabetta Teodori 5
Affiliations

Affiliations

  • 1 Department of Neuroscience, Psychology, Drug Research and Child's Health - Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
  • 2 Department of Health Sciences - Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy.
  • 3 Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, 50200, Thailand.
  • 4 Université Paris 13, Sorbonne Paris Cité, Laboratoire CSPBAT, CNRS (UMR 7244), UFR-SMBH, 74 rue Marcel Cachin, 93017 Bobigny, France.
  • 5 Department of Neuroscience, Psychology, Drug Research and Child's Health - Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy. Electronic address: elisabetta.teodori@unifi.it.
Abstract

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.

Keywords

Chemosensitizers; Doxorubicin-resistant human erythroleukemia K562 cells (K562/DOX); MDR reversers; P-gp modulators; Piperazine derivatives; Pirarubicin uptake.

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