Institut de Chimie, UMR 7177, University of Strasbourg/ CNRS, 4 rue Blaise Pascal, 67000, Strasbourg, France.
Department of Chemistry and Biochemistry, The University of Texas at Dallas, 800 W Campbell Rd., Richardson, TX, 75080, USA.
Angew Chem Int Ed Engl. 2020 May 11;59(20):7830-7835. doi: 10.1002/anie.201916316. Epub 2020 Mar 18.
Copper complexes are of medicinal and biological interest, including as anticancer drugs designed to cleave intracellular biomolecules by O activation. To exhibit such activity, the copper complex must be redox active and resistant to dissociation. Metallothioneins (MTs) and glutathione (GSH) are abundant in the cytosol and nucleus. Because they are thiol-rich reducing molecules with high Cu affinity, they are potential competitors for a copper ion bound in a copper drug. Herein, we report the investigation of a panel of Cu /Cu complexes often used as drugs, with diverse coordination chemistries and redox potentials. We evaluated their catalytic activity in ascorbate oxidation based on redox cycling between Cu and Cu , as well as their resistance to dissociation or inactivation under cytosolically relevant concentrations of GSH and MT. O -activating Cu /Cu complexes for cytosolic/nuclear targets are generally not stable against the GSH/MT system, which creates a challenge for their future design.
铜配合物具有医学和生物学意义，包括作为设计用于通过 O 激活裂解细胞内生物分子的抗癌药物。为了表现出这种活性，铜配合物必须具有氧化还原活性并且不易解离。金属硫蛋白（MTs）和谷胱甘肽（GSH）在细胞质和核中含量丰富。由于它们是富含巯基的还原分子，具有高铜亲和力，因此它们是与结合在铜药物中的铜离子竞争的潜在配体。在此，我们报告了对一组通常用作药物的 Cu/Cu 配合物的研究，这些配合物具有不同的配位化学和氧化还原电位。我们基于 Cu 和 Cu 之间的氧化还原循环评估了它们在抗坏血酸氧化中的催化活性，以及它们在细胞质相关浓度的 GSH 和 MT 下的解离或失活的抗性。用于细胞质/核靶标的 O 激活 Cu/Cu 配合物通常对 GSH/MT 系统不稳定，这对它们的未来设计提出了挑战。
