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 Aug 30;182:111655 Authors: Teodori E, Contino M, Riganti C, Bartolucci G, Braconi L, Manetti D, Romanelli MN, Trezza A, Athanasios A, Spiga O, Perrone MG, Giampietro R, Gazzano E, Salerno M, Colabufo NA, Dei S 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 characterist...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research