Sigma Receptor Ligands Carrying a Nitric Oxide Donor Nitrate Moiety: Synthesis, In Silico, and Biological Evaluation
Sigma Receptor Ligands Carrying a Nitric Oxide Donor Nitrate Moiety: Synthesis, In Silico, and Biological Evaluation
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DOI：
10.1021/acsmedchemlett.9b00661
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发表时间：
2020-05-14
影响因子：
4.2
通讯作者：
Prezzavento, Orazio
中科院分区：
文献类型：
--
作者：
Amata, Emanuele;Dichiara, Maria;Prezzavento, Orazio
我们报告了分子杂交体的开发，其中作为一氧化氮（NO）供体的硝酸根基团与sigma受体配体共价连接，为双靶向癌症治疗提供候选药物。化合物已在放射性配体结合测定法中在σ受体和所选化合物上进行了NO释放测试。对化合物9、15、18、19和21进行MTT测试。化合物15产生MCF-7和Caco-2细胞活力的显著降低，具有与阿霉素相当的IC 50，对成纤维细胞HFF-1细胞也没有毒性。化合物15显示出σ（1）受体拮抗剂/σ（2）受体激动剂特性。缺乏硝酸根基团的化合物15的两种衍生物不诱导MCF-7细胞活力的降低，表明σ受体和NO介导的事件之间的潜在协同效应。总之，NO供体和σ受体配体的组合提供了对癌症治疗具有有益效果的化合物。
We report the development of molecular hybrids in which a nitrate group serving as nitric oxide (NO) donor is covalently joined to sigma receptor ligands to give candidates for double-targeted cancer therapy. The compounds have been evaluated in radioligand binding assay at both sigma receptors and selected compounds tested for NO release. Compounds 9, 15, 18, 19, and 21 were subjected to MTT test. Compound 15 produced a significant reduction of MCF-7 and Caco-2 cellular viability with comparable IC50 as doxorubicin, being also not toxic for fibroblast HFF-1 cells. Compound 15 has shown a sigma(1), receptor antagonist/sigma(2) receptor agonist profile. Two derivatives of compound 15 lacking the nitrate group did not induce a reduction of MCF-7 cellular viability, suggesting a potential synergistic effect between the sigma receptors and the NO-mediated events. Overall, the combination of NO donor and sigma receptors ligands provided compounds with beneficial effects for the treatment of cancer.