The Davis Heart and Lung Research Institute, the Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
J Org Chem. 2013 Feb 15;78(4):1371-6. doi: 10.1021/jo301849k. Epub 2013 Feb 6.
In this work, we have developed a new class of dendritic TAM radicals (TG, TdG, and dTdG) through a convergent method based on the TAM core CT-03 or its deuterated analogue dCT-03 and trifurcated Newkome-type monomer. Among these radicals, dTdG exhibits the best EPR properties with sharpest EPR singlet and highest O(2) sensitivity due to deuteration of both the ester linker groups and the TAM core CT-03. Like the previous dendritic TAM radicals, these new compounds also show extremely high stability toward various reactive species owing to the dendritic encapsulation. The highly charged nature of these molecules resulting from nine carboxylate groups prevents concentration-dependent EPR line broadening at physiological pH. Furthermore, we demonstrate that these TAM radicals can be easily derivatized (e.g., PEGylation) at the nine carboxylate groups and the resulting PEGylated analogue dTdG-PEG completely inhibits the albumin binding, thereby enhancing suitability for in vivo applications. These new dendritic TAM radicals show great potential for in vivo EPR oximetric applications and provide insights on approaches to develop improved and targeted EPR oximetric probes for biomedical applications.
在这项工作中，我们通过基于 TAM 核心 CT-03 或其氘代类似物 dCT-03 和三叉形 Newkome 型单体的会聚方法开发了一类新型树枝状 TAM 自由基 (TG、TdG 和 dTdG)。在这些自由基中，由于酯键和 TAM 核心 CT-03 的两个氘代，dTdG 表现出最好的 EPR 性质，具有最尖锐的 EPR 单峰和最高的 O(2)灵敏度。与之前的树枝状 TAM 自由基一样，由于树枝状封装，这些新化合物也表现出对各种反应性物质的极高稳定性。由于九个羧酸盐基团的高度荷电性，这些分子具有很高的电荷性质，可防止在生理 pH 值下浓度依赖性 EPR 线展宽。此外，我们证明这些 TAM 自由基可以很容易地在九个羧酸盐基团上进行衍生化（例如聚乙二醇化），并且所得的聚乙二醇化类似物 dTdG-PEG 完全抑制白蛋白结合，从而增强了其在体内应用的适用性。这些新型树枝状 TAM 自由基在体内 EPR 血氧测定应用中具有很大的潜力，并为开发用于生物医学应用的改进和靶向 EPR 血氧测定探针提供了思路。
