Modulation of the spacer in N,N-bis(alkanol)amine aryl ester heterodimers led to the discovery of a series of highly potent P-glycoprotein-based multidrug resistance (MDR) modulators

• Published in: European journal of medicinal chemistry Vol. 172; pp. 71 - 94
• Main Authors: Dei, Silvia, Braconi, Laura, Trezza, Alfonso, Menicatti, Marta, Contino, Marialessandra, Coronnello, Marcella, Chiaramonte, Niccolò, Manetti, Dina, Perrone, Maria Grazia, Romanelli, Maria Novella, Udomtanakunchai, Chatchanok, Colabufo, Nicola Antonio, Bartolucci, Gianluca, Spiga, Ottavia, Salerno, Milena, Teodori, Elisabetta
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15-06-2019
• Subjects: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimmide hydrochloride; 4-Dimethylaminopyridine; Apparent permeability; ATPase activity; BCRP; BCRP modulators; Breast cancer resistance protein; Caco-2 cells; Colorectal adenocarcinoma cells; DMAP; DOX; Doxorubicin; EDCI; Human plasma stability; KEE; Ketoprofen Ethyl Ester; Madin-Darby Canin Kidney; MDCK; MDR reversers; Molecular docking; MRP1; MRP1 modulators; Multidrug resistance associated protein 1; P-glycoprotein; P-gp; P-gp modulators; PBS; PDB; Phosphate buffer solution; Pirarubicin uptake; Protein data bank; Rhd123; Rhodamine-123; Rhodamine-123 efflux; Topological polar surface area; TPSA; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimmide hydrochloride; BCRP modulators; 4-Dimethylaminopyridine; Doxorubicin; Breast cancer resistance protein; Molecular docking; PDB; Ketoprofen Ethyl Ester; MDR reversers; Colorectal adenocarcinoma cells; ATPase activity; DMAP; Pirarubicin uptake; MDCK; Rhodamine-123; PBS; BCRP; Human plasma stability; MRP1; P-gp; EDCI; Topological polar surface area; KEE; DOX; TPSA; P-glycoprotein; Protein data bank; Rhd123; P-gp modulators; Phosphate buffer solution; Madin-Darby Canin Kidney; MRP1 modulators; Multidrug resistance associated protein 1; Rhodamine-123 efflux; Apparent permeability; Caco-2 cells
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.03.054

In this study, a new series of N,N-bis(alkanol)amine aryl ester heterodimers was synthesized and studied. The new compounds were designed based on the structures of our previous arylamine ester derivatives endowed with high P-gp-dependent multidrug resistance reversing activity on a multidrug-resistant leukemia cell line. All new compounds were active in the pirarubicin uptake assay on the doxorubicin–resistant erythroleukemia K562 cells (K562/DOX). Compounds bearing a linker made up of 10 methylenes showed unprecedented high reversal activities regardless of the combination of aromatic moieties. Docking results obtained by an in silico study supported the data obtained by the biological tests and a study devoted to establish the chemical stability in phosphate buffer solution (PBS) and human plasma showed that only a few compounds exhibited a significant degradation in the human plasma matrix. Ten selected non-hydrolysable derivatives were able to inhibit the P-gp-mediated rhodamine-123 efflux on K562/DOX cells, and the evaluation of their apparent permeability and ATP consumption on other cell lines suggested that the compounds can behave as unambiguous or not transported substrates. The activity of these the compounds on the transport proteins breast cancer resistance protein (BCRP) and multidrug resistance associated protein 1 (MRP1) was also analyzed. All tested derivatives displayed a moderate potency on the BCRP overexpressing cells; while only four molecules showed to be effective on MRP1 overexpressing cells, highlighting a clear structural requirement for selectivity. In conclusion, we have identified a new very powerful series of compounds which represent interesting leads for the development of new potent and efficacious P-gp-dependent MDR modulators.
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•A new series of N,N-bis(alkanol)amine aryl esters was designed and synthesized.•The compounds were tested on K562/DOX cells in the pirarubicin uptake assay.•In silico studies and stability tests in PBS and human plasma were also performed.•Further experiments confirmed that they are P-gp-dependent MDR reversers.•A different selectivity vs sister proteins MRP1 and BCRP was highlighted.