Zampieri Daniele, Fortuna Sara, Calabretti Antonella, Romano Maurizio, Menegazzi Renzo, Schepmann Dirk, Wünsch Bernhard, Mamolo Maria Grazia
Department of Chemical and Pharmaceutical Sciences, P.le Europa 1-Via Giorgieri 1, University of Trieste, 34127 Trieste, Italy.
Department of Life Sciences, Via Valerio 28/1, University of Trieste, 34127 Trieste, Italy.
ACS Med Chem Lett. 2019 Dec 16;11(5):651-656. doi: 10.1021/acsmedchemlett.9b00524. eCollection 2020 May 14.
Among several potential applications, sigma receptor ligands can be used as antipsychotics, antiamnesics, and against other neurodegenerative disorders as well as neuroprotective agents. We present herein a new series of diazepane-containing derivatives as σR ligands obtained by a conformational expansion approach of our previously synthesized piperidine-based compounds. The best results were reached by benzofurane , and quinoline , -substituted diazepane derivatives, which showed the highest σR affinity. The cytotoxic activities of synthesized compounds were evaluated against two cancer cell lines, and the results indicated that none of the compounds induced significant toxicity in these cells. We also evaluated the antioxidant activity by radical scavenging capacity of our best compounds on ABTS and HO. The results obtained reveal that our new derivatives possess an excellent antioxidant profile and could be protective for the cells. Overall, the benzofurane derivative due to its strong interaction with the active site of the receptor, as confirmed by molecular dynamic simulations, emerged as the optimum compound with high σ1R affinity, low cytotoxicity, and a potent antioxidant activity.
在几种潜在应用中，σ受体配体可用作抗精神病药、抗遗忘药，用于对抗其他神经退行性疾病以及作为神经保护剂。我们在此展示了一系列新的含二氮杂环庚烷衍生物作为σR配体，它们是通过对我们之前合成的基于哌啶的化合物进行构象扩展方法得到的。苯并呋喃和喹啉取代的二氮杂环庚烷衍生物取得了最佳结果，显示出最高的σR亲和力。对合成化合物针对两种癌细胞系的细胞毒性活性进行了评估，结果表明这些化合物在这些细胞中均未诱导出显著毒性。我们还通过最佳化合物对ABTS和HO的自由基清除能力评估了其抗氧化活性。所获得的结果表明，我们的新衍生物具有优异的抗氧化特性，可能对细胞具有保护作用。总体而言，通过分子动力学模拟证实，苯并呋喃衍生物由于其与受体活性位点的强相互作用，成为具有高σ1R亲和力、低细胞毒性和强大抗氧化活性的最佳化合物。
