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
  • 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 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.