携带一氧化氮供体硝酸根部分的西格玛受体配体：合成、计算机模拟及生物学评价
Sigma Receptor Ligands Carrying a Nitric Oxide Donor Nitrate Moiety: Synthesis, In Silico, and Biological Evaluation.
作者信息
Amata Emanuele, Dichiara Maria, Gentile Davide, Marrazzo Agostino, Turnaturi Rita, Arena Emanuela, La Mantia Alfonsina, Tomasello Barbara Rita, Acquaviva Rosaria, Di Giacomo Claudia, Rescifina Antonio, Prezzavento Orazio
机构信息
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria, 95125 Catania, Italy.
Department of Drug Sciences, Chemistry Section, University of Catania, Viale A. Doria, 95125 Catania, Italy.
出版信息
ACS Med Chem Lett. 2020 Apr 9;11(5):889-894. doi: 10.1021/acsmedchemlett.9b00661. eCollection 2020 May 14.
Abstract
We report the development of molecular hybrids in which a nitrate group serving as nitric oxide (NO) donor is covalently joined to σ receptor ligands to give candidates for double-targeted cancer therapy. The compounds have been evaluated in radioligand binding assay at both σ receptors and selected compounds tested for NO release. Compounds , , , , and were subjected to MTT test. Compound produced a significant reduction of MCF-7 and Caco-2 cellular viability with comparable IC as doxorubicin, being also not toxic for fibroblast HFF-1 cells. Compound has shown a σ receptor antagonist/σ receptor agonist profile. Two derivatives of compound lacking the nitrate group did not induce a reduction of MCF-7 cellular viability, suggesting a potential synergistic effect between the σ receptors and the NO-mediated events. Overall, the combination of NO donor and σ receptors ligands provided compounds with beneficial effects for the treatment of cancer.
摘要
我们报道了分子杂化物的研发情况，其中作为一氧化氮（NO）供体的硝酸根与σ受体配体共价连接，从而得到用于双靶点癌症治疗的候选化合物。这些化合物已通过放射性配体结合试验对σ受体进行了评估，并且对选定的化合物进行了NO释放测试。化合物 、 、 、 和 进行了MTT试验。化合物 使MCF-7和Caco-2细胞活力显著降低，其IC与阿霉素相当，对成纤维细胞HFF-1细胞也无毒。化合物 呈现出σ受体拮抗剂/σ受体激动剂的特性。化合物 的两种不含硝酸根的衍生物未引起MCF-7细胞活力降低，这表明σ受体与NO介导的事件之间可能存在协同效应。总体而言，NO供体与σ受体配体的结合为癌症治疗提供了具有有益效果的化合物。
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