Dipartimento Farmacochimico, Università degli Studi di Bari ALDO MORO, Italy.
ChemMedChem. 2011 Jan 3;6(1):73-80. doi: 10.1002/cmdc.201000371.
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.
许多新的化疗药物正在进行临床前研究，尽管努力更有选择性地针对癌细胞，但往往会遇到毒性和固有耐药性等限制。因此，需要替代策略来治疗癌症并克服这些限制。我们描述了新型环己基哌嗪衍生物，这些衍生物被设计为同时与 sigma（σ）受体和人 Δ₈-Δ₇甾醇异构酶（HSI）结合的混合亲和力配体，同时还表现出 P-糖蛋白（P-gp）抑制活性，旨在利用 σ 和 HSI 位点介导的抗增殖作用，同时克服 P-gp 介导的耐药性。所有化合物均显示出对 σ 受体和 HSI 位点、P-gp 抑制活性和 σ₂ 受体激动剂抗增殖活性的高亲和力。还在 PC-3 细胞中测试了抗增殖活性，以确定 σ₁ 和 HSI 的贡献。化合物 cis-11 显示出最佳的抗增殖和 P-gp 抑制活性，与 0.1 μM 多柔比星在 MDCK-MDR1 细胞中共同给药。当以 30 μM 和 50 μM 共同给药时，化合物 cis-11 分别导致 70%和 90%的细胞死亡。当单独给药时，cis-11 导致 50%的细胞死亡，证明其在过表达 P-gp 的肿瘤细胞系中具有单药抗肿瘤特性。
