2. Academic Validation
  3. Design, synthesis and biological evaluation of stereo- and regioisomers of amino aryl esters as multidrug resistance (MDR) reversers

Design, synthesis and biological evaluation of stereo- and regioisomers of amino aryl esters as multidrug resistance (MDR) reversers

  • Eur J Med Chem. 2019 Nov 15:182:111655. doi: 10.1016/j.ejmech.2019.111655.
Elisabetta Teodori 1,  Marialessandra Contino 2,  Chiara Riganti 3,  Gianluca Bartolucci 4,  Laura Braconi 4,  Dina Manetti 4,  Maria Novella Romanelli 4,  Alfonso Trezza 5,  Asimidis Athanasios 5,  Ottavia Spiga 5,  Maria Grazia Perrone 2,  Roberta Giampietro 2,  Elena Gazzano 3,  Milena Salerno 6,  Nicola Antonio Colabufo 2,  Silvia Dei 4
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. Electronic address: elisabetta.teodori@unifi.it.
  • 2 Department of Pharmacy-Drug Sciences, University of Bari "A. Moro", via Orabona 4, 70125, Bari, Italy.
  • 3 Department of Oncology, University of Turin, Via Santena 5/bis, 10126, Torino, Italy.
  • 4 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.
  • 5 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.
  • 6 Université Paris 13, Sorbonne Paris Cité, Laboratoire CSPBAT, CNRS (UMR 7244), UFR-SMBH, 74 rue Marcel Cachin, 93017, Bobigny, France.
PMID: 31494468 DOI: 10.1016/j.ejmech.2019.111655
Abstract

Stereo- and regioisomers of a series of N,N-bis(alkanol)amine aryl ester derivatives have been prepared and studied as multidrug resistance (MDR) modulators. The new compounds contain a 2-(methyl)propyl chain combined with a 3-, 5- or 7-methylenes long chain and carry different aromatic ester portions. Thus, these compounds have a methyl group on the 3-methylenes chain and represent branched homologues of previously studied derivatives. The introduction of the methyl group gives origin to a stereogenic center and consequently to (R) and (S) enantiomers. In the pirarubicin uptake assay on K562/DOX cell line these compounds showed good activity and efficacy and in many cases enantioselectivity was observed. Docking studies confirmed the influence of the stereocenter on the interaction in the P-gp pocket. The P-gp interaction mechanism and selectivity towards MRP1 and BCRP were also evaluated on MDCK transfected cells overexpressing the three transporters. Almost all these compounds inhibited both P-gp and BCRP, but only derivatives with specific structural characteristics showed MRP1 activity. Moreover, two compounds, (S)-3 and (R)-7, showed the ability to induce collateral sensitivity (CS) against MDR cells. Therefore, these two CS-promoting agents could be considered interesting leads for the development of selective cytotoxic agents for drug-resistant cells.

Keywords

Collateral sensitivity; Enantiomers; Human plasma stability; K562 cells; MDCK cells; MDR reversers; Molecular docking; P-gp modulators.

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