1-Cyclohexyl-4-(4-arylcyclohexyl)piperazines: Mixed σ and human Δ(8)-Δ(7) sterol isomerase ligands with antiproliferative and P-glycoprotein inhibitory activity.

Many new chemotherapeutic agents are under preclinical investigation and, despite efforts to more selectively target cancer cells, limitations such as toxicity and inherent resistance are often encountered. Therefore, alternative strategies are needed to treat cancer and overcome such limitations. We describe novel cyclohexylpiperazine derivatives, designed as mixed affinity ligands for sigma (σ) receptors and human Δ₈-Δ₇ sterol isomerase (HSI) ligands, which also exhibit P-glycoprotein (P-gp) inhibitory activity, with the aim of exploiting the antiproliferative effects mediated by σ and HSI sites while overcoming P-gp-mediated resistance. All of the compounds displayed high affinities for σ receptors and HSI sites, P-gp inhibitory activity, and σ₂ receptor agonist antiproliferative activity. Antiproliferative activity was also tested in PC-3 cells to establish σ₁ and HSI contribution. Compound cis-11, which displayed the best antiproliferative and P-gp inhibitory activities, was co-administered with 0.1 μM doxorubicin in MDCK-MDR1 cells. Compound cis-11 caused 70 % and 90 % cell death when co-administered at 30 μM and 50 μm, respectively. When administered alone, cis-11 resulted in 50 % cell death, demonstrating its single agent antitumor properties in a tumor cell line overexpressing P-gp.