Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives.
Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives.
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DOI：
10.1021/jm400196q
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发表时间：
2013-10-24
影响因子：
7.3
通讯作者：
Miranda KM
中科院分区：
文献类型：
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作者：
Basudhar D;Bharadwaj G;Cheng RY;Jain S;Shi S;Heinecke JL;Holland RJ;Ridnour LA;Caceres VM;Spadari-Bratfisch RC;Paolocci N;Velázquez-Martínez CA;Wink DA;Miranda KM
非甾体抗炎药（NSAID）的结构修饰已成功降低胃肠道溃疡的副作用，而不影响抗炎活性，但长期使用可能会增加心肌梗死的风险。硝酰基（HNO）降低血小板聚集、对抗心肌梗死的先决条件和增强收缩性导致我们合成基于二醇二氮烯鎓的HNO释放阿司匹林并将其与NO释放类似物进行比较。在这里，这些化合物的分解机制进行了描述。除了对胃溃疡的保护之外，与阿司匹林或母体二醇二氮烯鎓相比，这些前药还表现出对非小细胞肺癌细胞（A549）的显著增强的细胞毒性，但对内皮细胞（HUVEC）没有明显的毒性。HNO-NSAID前药抑制环氧化酶-2和甘油醛3-磷酸脱氢酶活性，并触发显著的肌节缩短，与对照组相比，对小鼠心室肌细胞。总之，这些抗炎、抗肿瘤和收缩特性表明HNO-NSAID在治疗炎症、癌症或心力衰竭中的潜力。
Structural modifications of non-steroidal anti-inflammatory drugs (NSAIDs) have successfully reduced the side effect of gastrointestinal ulceration without affecting anti-inflammatory activity, but may increase risk of myocardial infarction with chronic use. That nitroxyl (HNO) reduces platelet aggregation, preconditions against myocardial infarction and enhances contractility led us to synthesize a diazeniumdiolate-based HNO releasing aspirin and to compare it to an NO-releasing analogue. Here, the decomposition mechanisms are described for these compounds. In addition to protection against stomach ulceration, these prodrugs also exhibited significantly enhanced cytotoxcity compared to either aspirin or the parent diazeniumdiolate toward non-small cell lung carcinoma cells (A549) but were not appreciably toxic toward endothelial cells (HUVECs). The HNO-NSAID prodrug inhibited cylcooxgenase-2 and glyceraldehyde 3-phosphate dehydrogenase activity and triggered significant sarcomere shortening compared to control on murine ventricular myocytes. Together, these anti-inflammatory, anti-neoplasic and contractile properties suggest the potential of HNO-NSAIDs in the treatment of inflammation, cancer or heart failure.