Department of Chemistry, Stony Brook University, 100 Nicolls Road, Stony Brook, New York 11794, United States.
Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States.
Inorg Chem. 2020 Nov 16;59(22):16095-16108. doi: 10.1021/acs.inorgchem.0c02314. Epub 2020 Oct 28.
A growing number of copper(II) complexes have been identified as suitable candidates for biomedical applications. Here, we show that the biocompatibility and stability of copper(II) complexes can be tuned by directed ligand design and complex geometry. We demonstrate that azamacrocycle-based chelators that envelope copper(II) in a five-coordinate, distorted trigonal-bipyramidal structure are more chemically inert to redox-mediated structural changes than their six-coordinate, Jahn-Teller-distorted counterparts, as evidenced by electrochemical, crystallographic, electron paramagnetic resonance, and density functional theory studies. We further validated our hypothesis of enhanced inertness in vitro and in vivo by employing Cu-64 radiolabeling of bifunctional analogues appended to a prostate-specific membrane antigen targeting dipeptide. The corresponding Cu-64 complexes were tested for stability in vitro and in vivo, with the five-coordinate system demonstrating the greatest metabolic stability among the studied picolinate complex series.
越来越多的铜（II）配合物被认为是适合生物医学应用的候选物。在这里，我们表明通过定向配体设计和配合物几何形状可以调整铜（II）配合物的生物相容性和稳定性。我们证明，与六配位、 Jahn-Teller 扭曲的同类物相比，五元配位、扭曲三角双锥结构的氮杂大环螯合剂在氧化还原介导的结构变化方面具有更高的化学惰性，这一点可以通过电化学、晶体学、电子顺磁共振和密度泛函理论研究得到证明。我们通过将前列腺特异性膜抗原靶向二肽连接的双功能类似物进行 Cu-64 放射性标记，进一步在体外和体内验证了我们假设的增强惰性。研究了相应的 Cu-64 配合物在体外和体内的稳定性，其中五配位体系在研究的吡啶甲酸配合物系列中表现出最大的代谢稳定性。
