As a continuation of a previous research, a series of N,N-bis(alkanol)amine aryl esters, as Pgp-dependent MDR inhibitors, was designed and synthesized. The aromatic ester portions are suitably modulated, and new aryl rings (Ar(1) and Ar(2)) were combined with trans-3-(3,4,5-trimethoxyphenyl)vinyl, 3,4,5-trimethoxybenzyl and anthracene moieties that were present in the most potent previously studied compounds. The new compounds showed a wide range of potencies and efficacies on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Selected compounds (5, 6, 8, 9, and 21) were further studied, evaluating their action on doxorubicin cytotoxicity potentiation on K562 cells; they significantly enhanced doxorubicin cytotoxicity on K562/DOX cells, confirming the results obtained with pirarubicin. Compound 9 shows the most promising properties as it was able to nearly completely reverse Pgp-dependent pirarubicin extrusion at nanomolar doses and increased the cytotoxicity of doxorubicin with a reversal fold (RF) of 19.1 at 3 microM dose.

Structure-activity relationships studies in a series of N,N-bis(alkanol)amine aryl esters as P-glycoprotein (Pgp) dependent multidrug resistance (MDR) inhibitors / Martelli, Cecilia; Coronnello, MARCELLA MARIA; Dei, Silvia; Manetti, Dina; Orlandi, Francesca; Scapecchi, Serena; Romanelli, MARIA NOVELLA; Salerno, M.; Mini, Enrico; Teodori, Elisabetta. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 53:(2010), pp. 1755-1762. [10.1021/jm9016174]

Structure-activity relationships studies in a series of N,N-bis(alkanol)amine aryl esters as P-glycoprotein (Pgp) dependent multidrug resistance (MDR) inhibitors

MARTELLI, CECILIA;CORONNELLO, MARCELLA MARIA;DEI, SILVIA;MANETTI, DINA;ORLANDI, FRANCESCA;SCAPECCHI, SERENA;ROMANELLI, MARIA NOVELLA;MINI, ENRICO;TEODORI, ELISABETTA
2010

Abstract

As a continuation of a previous research, a series of N,N-bis(alkanol)amine aryl esters, as Pgp-dependent MDR inhibitors, was designed and synthesized. The aromatic ester portions are suitably modulated, and new aryl rings (Ar(1) and Ar(2)) were combined with trans-3-(3,4,5-trimethoxyphenyl)vinyl, 3,4,5-trimethoxybenzyl and anthracene moieties that were present in the most potent previously studied compounds. The new compounds showed a wide range of potencies and efficacies on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Selected compounds (5, 6, 8, 9, and 21) were further studied, evaluating their action on doxorubicin cytotoxicity potentiation on K562 cells; they significantly enhanced doxorubicin cytotoxicity on K562/DOX cells, confirming the results obtained with pirarubicin. Compound 9 shows the most promising properties as it was able to nearly completely reverse Pgp-dependent pirarubicin extrusion at nanomolar doses and increased the cytotoxicity of doxorubicin with a reversal fold (RF) of 19.1 at 3 microM dose.
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1755
1762
Martelli, Cecilia; Coronnello, MARCELLA MARIA; Dei, Silvia; Manetti, Dina; Orlandi, Francesca; Scapecchi, Serena; Romanelli, MARIA NOVELLA; Salerno, M.; Mini, Enrico; Teodori, Elisabetta
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/381690
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