Institut de Chimie, UMR 7177, Université de Strasbourg, CNRS, 4 Rue Blaise Pascal, 67000, Strasbourg, France.
Institut Universitaire de France (IUF), 1 rue Descartes, 75231 Paris, France.
Dalton Trans. 2023 Feb 21;52(8):2197-2208. doi: 10.1039/d2dt03875g.
Metal ions play a very important role in nature and their homeostasis is crucial. A lot of metal-related chemical research activities are ongoing that concern metal-based drugs or tools, such as chelation therapy, metal- and metabolite sensors, metallo-drugs and prodrugs, PET and MRI imaging agents, . In most of these cases, the applied chelator/ligand (L) or metal-ligand complex (M-L) has at least to pass the blood plasma to reach the target. Hence it is exposed to several metal-binding proteins (mainly serum albumin and transferrin) and to all essential metal ions (zinc, copper, iron, .). This holds also for studies in cultured cells when fetal calf serum is used in the medium. There is a risk that the applied compound (L or M-L) in the serum is transformed into a different entity, due to trans-metallation and/or ligand exchange reactions. This depends on the thermodynamics and kinetics. For kinetically-labile complexes, the complex stability with all the ligands and all metal ions present in serum is decisive in evaluating the thermodynamic driving force towards a certain fate of the chelator or metal-ligand complex. To consider that, an integrative view is needed on the stability constants, by taking into account all the metal ions present and all the main proteins to which they are bound, as well as the non-occupied metal binding site in proteins. Only then, a realistic estimation of the complex stability, and hence its potential fate, can be done. This perspective aims to provide a simple approach to estimate the thermodynamic stability of labile metal-ligand complexes in a blood plasma/serum environment. It gives a guideline to obtain an estimation of the plasma and serum complex stability and metal selectivity starting from the chemical stability constants of metal-ligand complexes. Although of high importance, it does not focus on the more complex kinetic aspects of metal-transfer reactions. The perspective should help for a better design of such compounds, to perform test tube assays which are relevant to the conditions in the plasma/serum and to be aware of the importance of ternary complexes, kinetics and competition experiments.
金属离子在自然界中起着非常重要的作用，它们的体内平衡至关重要。目前正在进行大量与金属相关的化学研究活动，涉及基于金属的药物或工具，如螯合疗法、金属和代谢物传感器、金属药物和前药、正电子发射断层扫描（PET）和磁共振成像（MRI）造影剂等。在大多数情况下，应用的螯合剂/配体（L）或金属-配体络合物（M-L）至少要通过血浆才能到达靶标。因此，它会暴露于几种金属结合蛋白（主要是血清白蛋白和转铁蛋白）和所有必需的金属离子（锌、铜、铁等）。当在培养基中使用胎牛血清时，这也适用于培养细胞的研究。由于转金属化和/或配体交换反应，应用于血清中的化合物（L 或 M-L）有可能转化为不同的实体，这存在风险。这取决于热力学和动力学。对于动力学不稳定的配合物，与血清中存在的所有配体和所有金属离子的配合物稳定性对于评估配体或金属-配体配合物向特定命运的热力学驱动力是决定性的。为了考虑这一点，需要考虑稳定性常数的综合观点，同时考虑到存在的所有金属离子和它们结合的所有主要蛋白质，以及蛋白质中未占据的金属结合位点。只有这样，才能对配合物的稳定性进行真实的估计，从而对其潜在命运进行估计。本文旨在提供一种简单的方法来估计在血浆/血清环境中不稳定的金属-配体配合物的热力学稳定性。它提供了一种从金属-配体配合物的化学稳定性常数出发，获得对血浆和血清配合物稳定性和金属选择性的估计的指南。虽然这一点非常重要，但它并不关注金属转移反应更复杂的动力学方面。该方法有助于更好地设计此类化合物，进行与血浆/血清条件相关的试管试验，并认识到三元配合物、动力学和竞争实验的重要性。
