2. Academic Validation
  3. Multidrug resistance (MDR) reversers: High activity and efficacy in a series of asymmetrical N,N-bis(alkanol)amine aryl esters

Multidrug resistance (MDR) reversers: High activity and efficacy in a series of asymmetrical N,N-bis(alkanol)amine aryl esters

  • Eur J Med Chem. 2014 Nov 24:87:398-412. doi: 10.1016/j.ejmech.2014.09.084.
Silvia Dei 1,  Marcella Coronnello 2,  Elisa Floriddia 3,  Gianluca Bartolucci 3,  Cristina Bellucci 3,  Luca Guandalini 3,  Dina Manetti 3,  Maria Novella Romanelli 3,  Milena Salerno 4,  Ivan Bello 4,  Enrico Mini 2,  Elisabetta Teodori 3
Affiliations

Affiliations

  • 1 Dipartimento NEUROFARBA-Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy. Electronic address: silvia.dei@unifi.it.
  • 2 Dipartimento di Scienze della Salute, Università di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy.
  • 3 Dipartimento NEUROFARBA-Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
  • 4 Université Paris 13, Sorbonne Paris Cité, Laboratoire CSPBAT, CNRS (UMR 7244), UFR-SMBH, 74 Rue Marcel Cachin, 93017 Bobigny, France.
PMID: 25282263 DOI: 10.1016/j.ejmech.2014.09.084
Abstract

As a continuation of our research on potent and efficacious P-gp-dependent multidrug resistance (MDR) reversers, several new N,N-bis(alkanol)amine aryl esters were designed and synthesized, varying the aromatic moieties or the length of the methylenic chain. The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay, where most of the new compounds were shown to be active. In particular the asymmetrical compounds, characterized by two linkers of different length, generally showed fairly high activities as MDR reversers. Some selected compounds (isomers 15-17) were further studied by evaluating their doxorubicin cytotoxicity enhancement (reversal fold, RF) on the K562/DOX cell line. The results of both pharmacological assays indicate that compounds 16 (GDE6) and 17 (GDE19) could be interesting leads for the development of new P-gp dependent MDR modulators.

Keywords

Chemosensitizers; Doxorubicin-resistant erythroleukemia K562 cells (K562/DOX); MDR reversers; N,N-bis(alkanol)amine aryl esters; P-gp inhibitors; Pirarubicin uptake.

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