N-alkanol-N-cyclohexanol amine aryl esters: Multidrug resistance (MDR) reversing agents with high potency and efficacy

  • Eur J Med Chem. 2017 Feb 15;127:586-598. doi: 10.1016/j.ejmech.2017.01.019.
Elisabetta Teodori  1 ,  Silvia Dei  2 ,  Marcella Coronnello  3 ,  Elisa Floriddia  2 ,  Gianluca Bartolucci  2 ,  Dina Manetti  2 ,  Maria Novella Romanelli  2 ,  Diego Santo Domingo Porqueras  4 ,  Milena Salerno  4
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. Electronic address: [email protected].
  • 2. 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.
  • 3. Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy.
  • 4. Université Paris 13, Sorbonne Paris Cité, Laboratoire CSPBAT, CNRS (UMR 7244), UFR-SMBH, 74 rue Marcel Cachin, 93017 Bobigny, France.
PMID: 28113128 DOI: 10.1016/j.ejmech.2017.01.019
Abstract

In a continuing search for potent P-gp-dependent multidrug-resistant (MDR) reversers we synthesized and studied a new series of N-alkanol-N-cyclohexanol amine aryl esters characterized by the presence of two linkers with different flexibility: a polymethylene chain of variable length and a cyclohexylic scaffold, that gave origin to two geometrical isomers (cis and trans). The reversal activity of the new compounds was evaluated on the K562/DOX cell line by three tests: pirarubicin uptake modulation, doxorubicin cytotoxicity enhancement (reversal fold, RF) and inhibition of P-gp-mediated rhodamine-123 (Rhd 123) efflux tests. The chemical stability of their ester function was evaluated in the experimental conditions utilized (phosphate buffer solution (PBS), bovine serum and in the presence of K562/DOX cells) and in human plasma. The new series of molecules showed very interesting MDR reversing properties; in particular compound 5b (ELF26B), characterized by trans stereochemistry and a 5-methylene chain, presented the best pharmacological profile and is stable in each tested medium. Compound 5b could be an interesting lead for the development of new potent and efficacious P-gp-dependent MDR modulators.

Keywords
Chemosensitizers; Doxorubicin-resistant human erythroleukemia K562 cells (K562/DOX); MDR reversers; N-alkanol-N-cyclohexanol amine aryl esters; P-gp modulators; Pirarubicin uptake.
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