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Editor-in-Chief: Natalia Ortúzar
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Online ISSN: 1860-7187
November 11, 2010
VIP: 1-Cyclohexyl-4-(4-arylcyclohexyl)piperazines: Mixed σ and Δ8–Δ7 Sterol Isomerase Ligands with Antiproliferative and P-Glycoprotein Inhibitory Activity
Carmen Abate,* Mauro Niso, Marialessandra Contino, Nicola Antonio Colabufo, Savina Ferorelli, Roberto Perrone, and Francesco Berardi
Many new chemotherapeutic agents are under preclinical investigation, and despite efforts to target cancer more specifically, limitations such as toxicity and inherent resistance are often encountered. Therefore, alternative strategies are needed to and overcome such limitations in cancer treatment. A research project conducted by Carmen Abate and colleagues at the University of Bari (Italy) led to a novel class of compounds—cyclohexylpiperazine derivatives—designed to act simultaneously at different targets involved in cancer, such as σ-1 and σ-2 receptors, human Δ8–Δ7 sterol isomerase (HSI), and the efflux pump P-glycoprotein (P-gp).
The antiproliferative effect mediated by σ receptors and HSI sites, evaluated in cancer cell lines, was accompanied by convenient inhibitory activity toward P-gp, so that these compounds showed an ability to overcome P-gp-mediated resistance. Abate and co-workers demonstrated that the compound with the best antiproliferative/P-gp inhibitory activities displays single-agent antitumor properties, reverting P-gp-mediated resistance while triggering antiproliferative effects at the same time. Abate's research group plans to follow this with in vivo studies to test the efficacy of these promising multi-target agents, the synergic antiproliferative action of which, combined with inhibitory P-gp activity, imparts them the potential for use either as antitumor agents devoid of P-gp-mediated resistance, or in association with classic antitumor agents susceptible to P-gp activity.
Received September 2, 2010; published online November 10, 2010, DOI: 10.1002/cmdc.201000371.