Multifaceted activity of polyciclic MDR revertant agents in drug-resistant leukemic cells: Role of the spacer

[Display omitted] •A series of polycyclic derivatives was optimized to find potent chemosensitizers.•3d and 3e proved to be potent MDR reverting agents.•3e establishes a strong H-bond with a key residue for P-gp binding and functioning.•A multifaceted anticancer profile was identified for most of the new compounds.•3c is a multipotent MDR reverting/cytotoxic compound, endowed with a CS profile. A small library of derivatives carrying a polycyclic scaffold recently identified by us as a new privileged structure in medicinal chemistry was designed and synthesized, aiming at obtaining potent MDR reverting agents also endowed with antitumor properties. In particular, as a follow-up of our previous studies, attention was focused on the role of the spacer connecting the polycyclic core with a properly selected nitrogen-containing group. A relevant increase in reverting potency was observed, going from the previously employed but-2-ynyl- to a pent-3-ynylamino moiety, as in compounds 3d and 3e, while the introduction of a triazole ring proved to differently impact on the activity of the compounds. The docking results supported the data obtained by biological tests, showing, for the most active compounds, the ability to establish specific bonds with P-glycoprotein. Moreover, a multifaceted anticancer profile and dual in vitro activity was observed for all compounds, showing both revertant and antitumor effects on leukemic cells. In this respect, 3c emerged as a “triple-target” agent, endowed with a relevant reverting potency, a considerable antiproliferative activity and a collateral sensitivity profile.