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首页> 外文期刊>Dalton transactions: An international journal of inorganic chemistry >Modulation of drug activation profiles through carboxylate ligand modification in cytotoxic trans-platinum planar amine compounds
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Modulation of drug activation profiles through carboxylate ligand modification in cytotoxic trans-platinum planar amine compounds

机译：通过细胞毒性反铂平面胺化合物中的羧酸酯配体修饰来调节药物活化曲线

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Transplatinum planaramine (TPA) compounds possessing carboxylate ligands in the trans position have been shown to be potential antitumor drugs in a variety of cell types, including cisplatin and oxaliplatin-resistant cell lines. In this work, we ask whether the nature and stability of the carboxylate ligand can be tuned in an attempt to manipulate the extent of serum protein binding; and consequently influence cytotoxicity, cellular drug accumulation and DNA adduct formation. Monitoring the interactions of selected TPAs with N-acetyl-methionine (NAM) by ~1H and ~(195)Pt NMR spectroscopy shows significant differences in the rate of sulfur binding. TPA-containing acetate ligands show a much lower sulfur binding rate than those possessing formate leaving groups. The same trend was seen when acetate and formate TPA compounds were incubated with human serum albumin and the reaction monitored for 24 h. To understand whether these results could be translated into a cellular medium, MTT cytotoxicity assays were conducted for each compound, before and after incubation with whole serum. Both the formate and acetate compounds, t-[Pt(4-pic)NH_3(OFm)_2] and t-[Pt(4-pic)NH _3(OAc)_2], showed minimal losses in cytotoxic efficacy and outperformed cisplatin after pre-incubation with serum. The same trends were seen when monitoring the effects of protein binding on cellular uptake and DNA platination. The rate of protein binding/drug deactivation was shown to be directly related to the stability of the leaving group (OAc~- > OFm~- > Cl~-). Thus, our results suggest that utilization of the 'carboxylate strategy' substantially enhances the cellular efficacy of TPA compounds over cisplatin by allowing for an optimal balance between cytotoxic and metabolic efficiency.
机译：在反式位置具有羧酸盐配体的反式铂胺（TPA）化合物已被证明在包括顺铂和奥沙利铂抗性细胞系在内的多种细胞类型中是潜在的抗肿瘤药物。在这项工作中，我们问羧酸盐配体的性质和稳定性是否可以调整，以试图控制血清蛋白结合的程度;因此会影响细胞毒性，细胞药物蓄积和DNA加合物的形成。通过〜1H和〜（195）Pt NMR光谱监测选定的TPA与N-乙酰基甲硫氨酸（NAM）的相互作用，发现硫结合速率存在显着差异。含有TPA的乙酸酯配体比具有甲酸酯离去基团的硫结合率低得多。当乙酸盐和甲酸盐TPA化合物与人血清白蛋白一起孵育并监测反应24小时时，可以看到相同的趋势。为了理解这些结果是否可以转化为细胞培养基，在与全血清孵育之前和之后对每种化合物进行了MTT细胞毒性测定。甲酸盐和乙酸盐化合物t- [Pt（4-pic）NH_3（OFm）_2]和t- [Pt（4-pic）NH _3（OAc）_2]均显示出最小的细胞毒性损失，且顺铂的作用优于与血清预孵育。监测蛋白质结合对细胞摄取和DNA平台化的影响时，可以看到相同的趋势。已证明蛋白质结合/药物失活的速率与离去基团的稳定性直接相关（OAc--> OFm--> Cl--）。因此，我们的结果表明，“羧酸盐策略”的利用通过在细胞毒性和代谢效率之间实现了最佳平衡，大大增强了TPA化合物相对于顺铂的细胞功效。

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