A new series of Pgp-dependent MDR inhibitors having a N,N-bis(cyclohexanol)amine scaffold was designed on the basis of the frozen analogue approach. The scaffold chosen gives origin to different geometrical isomers. The new compounds showed a wide range of potencies and efficacies on doxorubicin-resistant erythroleukemia K562 cells in the pirarubicin uptake assay. The most interesting compounds (isomers of 3) were studied further evaluating their action on the ATPase activity present in rat small intestine membrane vesicles and doxorubicin cytotoxicity potentiation on K562 cells. The latter assay was performed also on the isomers of 4. The four isomers of each set present different behavior in each of these tests. Compound 3d shows the most promising properties as it was able to completely reverse Pgp-dependent pirarubicin extrusion at low nanomolar concentration, inhibited ATPase activity at 5 × 10-9 and increased the cytotoxicity of doxorubicin with a reversal fold (RF) of 36.4 at 3 μM concentration.

N,N-bis(cyclohexanol)amine aryl esters: a new class of highly potent Pgp-dependent multidrug resistance (MDR) inhibitors / Martelli, Cecilia; Alderighi, Daniela; Coronnello, MARCELLA MARIA; Dei, Silvia; Frosini, Maria; Bozec, Benedicte Le; Manetti, Dina; Neri, Annalisa; Romanelli, MARIA NOVELLA; Salerno, Milena; Scapecchi, Serena; Mini, Enrico; Sgaragli, Giampietro; Teodori, Elisabetta. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 52(2009), pp. 807-817. [10.1021/jm8012745]

N,N-bis(cyclohexanol)amine aryl esters: a new class of highly potent Pgp-dependent multidrug resistance (MDR) inhibitors

MARTELLI, CECILIA;CORONNELLO, MARCELLA MARIA;DEI, SILVIA;MANETTI, DINA;ROMANELLI, MARIA NOVELLA;SCAPECCHI, SERENA;MINI, ENRICO;TEODORI, ELISABETTA
2009

Abstract

A new series of Pgp-dependent MDR inhibitors having a N,N-bis(cyclohexanol)amine scaffold was designed on the basis of the frozen analogue approach. The scaffold chosen gives origin to different geometrical isomers. The new compounds showed a wide range of potencies and efficacies on doxorubicin-resistant erythroleukemia K562 cells in the pirarubicin uptake assay. The most interesting compounds (isomers of 3) were studied further evaluating their action on the ATPase activity present in rat small intestine membrane vesicles and doxorubicin cytotoxicity potentiation on K562 cells. The latter assay was performed also on the isomers of 4. The four isomers of each set present different behavior in each of these tests. Compound 3d shows the most promising properties as it was able to completely reverse Pgp-dependent pirarubicin extrusion at low nanomolar concentration, inhibited ATPase activity at 5 × 10-9 and increased the cytotoxicity of doxorubicin with a reversal fold (RF) of 36.4 at 3 μM concentration.
52
807
817
Martelli, Cecilia; Alderighi, Daniela; Coronnello, MARCELLA MARIA; Dei, Silvia; Frosini, Maria; Bozec, Benedicte Le; Manetti, Dina; Neri, Annalisa; Romanelli, MARIA NOVELLA; Salerno, Milena; Scapecchi, Serena; Mini, Enrico; Sgaragli, Giampietro; Teodori, Elisabetta
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2158/351405
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