N,N-bis(Cyclohexanol)amine Aryl Esters: The Discovery of a New Class of Highly Potent Inhibitors of ransporter-Dependent Multidrug Resistance (MDR)

Multidrug resistance (MDR) is a kind of acquired resistance of microorganisms and cancer cells to chemotherapeutic drugs that are characterized by different chemical structure and different mechanism of action. Classic MDR is due to a lower intracellular concentration of cytotoxic drugs that is associated with accelerated efflux of the chemotherapeutic drugs and is the consequence of the over expression of transporter proteins that act as extrusion pumps. Pglycoprotein (P-gp/ABCB1) is the most important and studied member of such proteins belonging to the ATP Binding Cassette (ABC) superfamily of transporters that use ATP as energy source. Inhibition of the functions of P-gp and other ABC proteins could represent a way to circumvent appearance of MDR in cancer cells and the most classical pharmacological strategy is the administration of agents able to modulate the P-gp function. On the basis of the known characteristics of the recognition site of P-gp, we have designed a new class of P-gp-mediated MDR reverters. These compounds are flexible molecules carrying a basic nitrogen atom flanked, at properly modulated distance, by two aromatic moieties; most of them possess MDR inhibitory activity on anthracycline-resistant erytroleukemia K562 cells. By applying the frozen analog approach to that series of very flexible MDR reverters, we identified a new series of N,N-bis(cyclohexanol)amine aryl esters that show very interesting MDR-reversing properties. Among them, compound 15d, that consistently shows low nanomolar potency and high efficacy in all the tests used, appears as a new pharmacological tool for P-gp studies and a promising lead for the development of potent, efficient and safe MDR reverters.