The hydrolysis mechanism of the anticancer ruthenium drugs NAMI-A and ICR investigated by DFT-PCM calculations.
The hydrolysis mechanism of the anticancer ruthenium drugs NAMI-A and ICR investigated by DFT-PCM calculations.
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DOI：
10.1021/jp710078y
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发表时间：
2008-03
期刊：
影响因子：
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通讯作者：
A. Vargiu;Arturo Robertazzi;A. Magistrato;P. Ruggerone;P. Carloni
中科院分区：
文献类型：
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作者：
A. Vargiu;Arturo Robertazzi;A. Magistrato;P. Ruggerone;P. Carloni
（ImH）[trans-RuCl(4)(DMSO-S)(Im)], （Im =咪唑，DMSO-S = s键二甲基亚砜），NAMI-A是第一个成功完成I期临床试验的抗癌钌化合物。NAMI-A对实体瘤肺转移有显著的抑制作用，但对原发肿瘤的抑制作用不明显。结构相似的（ImH）[trans-RuCl(4)(Im)(2)]， ICR（或KP418）及其吲哚唑类似物（KP1019）是治疗结直肠癌的有希望的候选药物，但没有抗转移活性。尽管这些化合物具有药理意义，但没有任何理论依据来解释它们明显不同的活性。虽然其抗转移/抗癌活性的化学物质的性质尚未确定，但有人认为NAMI-A和ICR的还原电位之间的差异可能是它们诱导的不同生物反应的关键。在这项工作中，密度泛函理论计算进行了研究在Ru（III）和Ru（II）氧化态下NAMI-A和ICR的水解，直到第三水化。与实验结果一致，我们的计算提供了NAMI-A和ICR水解的图像，主要是氯配体的逐步损失。虽然Im在中性条件下不太可能解离，但随着水解的进行，DMSO的解离与氯离子的损失形成竞争。研究了NAMI-A和ICR及其最相关的水解中间体的氧化还原特性，以监测生物还原剂对其作用机制的影响。我们的发现可能有助于鉴定与生物靶点相互作用的活性化合物，并解释NAMI-A和ICR不同的生物活性。
(ImH)[trans-RuCl(4)(DMSO-S)(Im)], (Im = imidazole, DMSO-S = S-bonded dimethylsulfoxide), NAMI-A, is the first anticancer ruthenium compound that successfully completed Phase I clinical trials. NAMI-A shows a remarkable activity against lung metastases of solid tumors, but is not effective in the reduction of primary cancer. The structurally similar (ImH)[trans-RuCl(4)(Im)(2)], ICR (or KP418), and its indazole analog (KP1019) are promising candidate drugs in the treatment of colorectal cancers, but have no antimetastatic activity. Despite the pharmacological relevance of these compounds, no rationale has been furnished to explain their markedly different activity. While the nature of the chemical species responsible for their antimetastatic/anticancer activity has not been determined, it has been suggested that the difference between reduction potentials of NAMI-A and ICR may be the key to the different biological responses they induce. In this work, Density Functional Theory calculations were performed to investigate the hydrolysis of NAMI-A and ICR in both Ru(III) and Ru(II) oxidation states, up to the third aquation. In line with experimental findings, our calculations provide a picture of the hydrolysis of NAMI-A and ICR mainly as a stepwise loss of chloride ligands. While dissociation of Im is unlikely under neutral conditions, that of DMSO becomes competitive with the loss of chloride ions as the hydrolysis proceeds. Redox properties of NAMI-A and ICR and of their most relevant hydrolytic intermediates were also studied in order to monitor the effects of biological reductants on the mechanism of action. Our findings may contribute to the identification of the active compounds that interact with biological targets, and to explain the different biological activity of NAMI-A and ICR.