N,N-bis(Cyclohexanol)amine Aryl Esters: A New Class of Highly Potent Transporter-Dependent Multidrug Resistance Inhibitors

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• 作者：Cecilia Martelli ; Daniela Alderighi ; Marcella Coronnello ; Silvia Dei ; Maria Frosini ; Bndicte Le Bozec ; Dina Manetti ; Annalisa Neri ; Maria Novella Romanelli ; Milena Salerno ; Serena Scapecchi ; Enrico Mi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：February 12, 2009
• 年：2009
• 卷：52
• 期：3
• 页码：807-817
• 全文大小：263K
• 年卷期：v.52,no.3(February 12, 2009)
• ISSN：1520-4804

文摘

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.