JBIC Journal of Biological Inorganic Chemistry ( IF 2.7 ) Pub Date : 2022-09-25 , DOI: 10.1007/s00775-022-01958-z Fang-Xin Wang 1, 2 , Ivan Prokes 1 , Lijiang Song 1 , Huayun Shi 1 , Peter J Sadler 1
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Determination of the toxicity of compounds toward cancer cells is a frequent procedure in drug discovery. For metal complexes, which are often reactive prodrugs, care has to be taken to consider reactions with components of the cell culture medium that might change the speciation of the metal complex before it is taken up by the cells. Here, we consider possible reactions between the clinical platinum drugs cisplatin and oxaliplatin with penicillin G, an antibiotic added routinely to cell culture media to prevent bacterial contamination. Platinum has a high affinity for ligands with sulfur donors. Penicillin G is an unstable thioether that degrades in a range of pathways. Nuclear magnetic resonance (NMR) and UV–Vis absorption spectroscopic studies show that reactions with cisplatin can occur within minutes to hours at 310 K, but more slowly with oxaliplatin. The identities of the Pt- adducts were investigated by mass spectrometry. The marked effect on cytotoxicity of co-incubation of cisplatin with penicillin G was demonstrated for the HeLa human cervical cancer cell line. These studies highlight the possibility that reactions with penicillin G might influence the cytotoxic activity of metal complexes determined in culture media.
Graphical abstract
中文翻译：
顺铂和奥沙利铂与青霉素 G 的反应：对药物失活和生物活性的影响
确定化合物对癌细胞的毒性是药物发现中的常见程序。对于通常是反应性前体药物的金属络合物，必须小心考虑与细胞培养基成分的反应，这些反应可能会在金属络合物被细胞吸收之前改变其形态。在这里，我们考虑了临床铂类药物顺铂和奥沙利铂与青霉素 G 之间可能发生的反应，青霉素 G 是一种常规添加到细胞培养基中以防止细菌污染的抗生素。铂对含硫供体的配体具有高亲和力。青霉素 G 是一种不稳定的硫醚，会在一系列途径中降解。核磁共振 (NMR) 和紫外-可见吸收光谱研究表明，在 310 K 时，与顺铂的反应可在数分钟至数小时内发生，但用奥沙利铂更慢。Pt-加合物的身份通过质谱法研究。顺铂与青霉素 G 共孵育对 HeLa 人宫颈癌细胞系的细胞毒性有显着影响。这些研究强调了与青霉素 G 的反应可能影响在培养基中测定的金属络合物的细胞毒活性的可能性。
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