Gold-based compounds are of great interest in the field of medicinal chemistry as novel therapeutic (anticancer) agents due to their peculiar reactivity and mechanisms of action with respect to organic drugs. Despite their promising pharmacological properties, the possible toxic effects of gold compounds need to be carefully evaluated in order to optimize their design and applicability. This study reports on the potential toxicity of three experimental gold-based anticancer compounds featuring lansoprazole ligands (1–3) studied in an ex vivo model, using rat precision cut kidney and liver slices (PCKS and PCLS, respectively). The results showed a different toxicity profile for the tested compounds, with the neutral complex 2 being the least toxic, even less toxic than cisplatin, followed by the cationic complex 1. The dinuclear cationic gold complex 3 was the most toxic in both liver and kidney slices. This result correlated with the metal uptake of the different compounds assessed by ICP-MS, where complex 3 showed the highest accumulation of gold in liver and kidney slices. Interestingly compound 1 showed the highest selectivity towards cancer cells compared to the healthy tissues. Histomorphology evaluation showed a similar pattern for all three Au(I) complexes, where the distal tubular cells suffered the most extensive damage, in contrast to the damage in the proximal tubules induced by cisplatin. The binding of representative gold compounds with the model ubiquitin was also studied by ESI-MS, showing that after 24 h incubation only ‘naked’ Au ions were bound to the protein following ligands’ loss. The mRNA expression of stress response genes appeared to be similar for both evaluated organs, suggesting oxidative stress as the possible mechanism of toxicity. The obtained results open new perspectives towards the design and testing of bifunctional gold complexes with chemotherapeutic applications.

中文翻译：

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具有兰索拉唑型配体的实验性抗癌金（i）配合物的离体毒理学评估。

基于金的化合物由于其独特的反应性和相对于有机药物的作用机理，在药物化学领域作为新型治疗（抗癌）药物引起了人们的极大兴趣。尽管它们具有令人满意的药理特性，但仍需仔细评估金化合物可能产生的毒性作用，以优化其设计和适用性。这项研究报告了在离体模型中研究的三种具有兰索拉唑配体的实验性金基抗癌化合物（1-3）的潜在毒性，该化合物使用大鼠精确切开的肾脏和肝脏切片（分别为PCKS和PCLS）。结果显示，中性配合物2对受试化合物的毒性不同。具有最小的毒性，甚至比顺铂的毒性更小，其次是阳离子配合物1。双核阳离子金络合物3在肝脏和肾脏切片中毒性最高。该结果与通过ICP-MS评估的不同化合物对金属的吸收有关，其中复合物3在肝脏和肾脏切片中显示出最高的金积累。有趣的是，与健康组织相比，化合物1对癌细胞的选择性最高。组织形态学评估显示所有三种Au（I）复合物，其中远端小管细胞受到最广泛的破坏，与顺铂引起的近端小管破坏相反。还通过ESI-MS研究了具有代表性的金化合物与泛素模型的结合，结果表明在孵育24小时后，配体丢失后仅“裸”金离子与蛋白质结合。应激反应基因的mRNA表达对于两个评估器官似乎相似，表明氧化应激是毒性的可能机制。获得的结果为双功能金配合物在化学治疗中的设计和测试开辟了新的前景。