Seixas João D, Chaves-Ferreira Miguel, Montes-Grajales Diana, Gonçalves Ana M, Marques Ana R, Saraiva Lígia M, Olivero-Verbel Jesus, Romão Carlos C, Bernardes Gonçalo J L
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa (Portugal) www.gbernardes-lab.com.
Instituto de Tecnologia Química e Biológica-António Xavier, Universidade Nova de Lisboa, Av da República, 2780-157 Oeiras (Portugal).
Chemistry. 2015 Oct 12;21(42):14708-12. doi: 10.1002/chem.201502474. Epub 2015 Aug 28.
We have designed and synthesised a [Ru(CO)3 Cl2 (NAC)] pro-drug that features an N-acetyl cysteine (NAC) ligand. This NAC carbon monoxide releasing molecule (CORM) conjugate is able to simultaneously release biologically active CO and to ablate the concurrent formation of reactive oxygen species (ROS). Complexes of the general formulae Ru(CO)3 (L)3 , including [Ru(CO)3 Cl(glycinate)] (CORM-3), have been shown to produce ROS through a water-gas shift reaction, which contributes significantly, for example, to their antibacterial activity. In contrast, NAC-CORM conjugates do not produce ROS or possess antibacterial activity. In addition, we demonstrate the synergistic effect of CO and NAC both for the inhibition of nitric oxide (formation) and in the expression of tumour-necrosis factor (TNF)-α. This work highlights the advantages of combining a CO-releasing scaffold with the anti-oxidant and anti-inflammatory drug NAC in a unique pro-drug.
我们设计并合成了一种具有N - 乙酰半胱氨酸（NAC）配体的[Ru(CO)3 Cl2 (NAC)]前药。这种NAC一氧化碳释放分子（CORM）共轭物能够同时释放生物活性CO，并消除活性氧（ROS）的同时形成。通式为Ru(CO)3 (L)3 的配合物，包括[Ru(CO)3 Cl(glycinate)]（CORM - 3），已被证明通过水煤气变换反应产生活性氧，例如，这对它们的抗菌活性有显著贡献。相比之下，NAC - CORM共轭物不产生活性氧或具有抗菌活性。此外，我们证明了CO和NAC在抑制一氧化氮（生成）以及肿瘤坏死因子（TNF）-α表达方面的协同作用。这项工作突出了在独特的前药中将CO释放支架与抗氧化和抗炎药物NAC相结合的优势。
