Schmies Constanze C, Rolshoven Georg, Idris Riham M, Losenkova Karolina, Renn Christian, Schäkel Laura, Al-Hroub Haneen, Wang Yulu, Garofano Francesca, Schmidt-Wolf Ingo G H, Zimmermann Herbert, Yegutkin Gennady G, Müller Christa E
PharmaCenter Bonn, Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
MediCity Research Laboratory, University of Turku, 20520 Turku, Finland.
ACS Med Chem Lett. 2020 Sep 3;11(11):2253-2260. doi: 10.1021/acsmedchemlett.0c00391. eCollection 2020 Nov 12.
Ecto-5'-nucleotidase (CD73) catalyzes the hydrolysis of AMP to anti-inflammatory, immunosuppressive adenosine. It is expressed on vascular endothelial, epithelial, and also numerous cancer cells where it strongly contributes to an immunosuppressive microenvironment. In the present study we designed and synthesized fluorescent-labeled CD73 inhibitors with low nanomolar affinity and high selectivity based on benzyl-α,β-methylene-ADP (PSB-12379) as a lead structure. Fluorescein was attached to the benzyl residue via different linkers resulting in PSB-19416 (, 12.6 nM) and PSB-18332 (, 2.98 nM) as fluorescent high-affinity probes for CD73. These compounds are anticipated to become useful tools for biological studies, drug screening, and diagnostic applications.
胞外5'-核苷酸酶（CD73）催化AMP水解为具有抗炎、免疫抑制作用的腺苷。它在血管内皮细胞、上皮细胞以及众多癌细胞上表达，在这些细胞中它对免疫抑制微环境有重要作用。在本研究中，我们基于苄基-α,β-亚甲基-ADP（PSB-12379）作为先导结构，设计并合成了具有低纳摩尔亲和力和高选择性的荧光标记CD73抑制剂。荧光素通过不同的连接子连接到苄基残基上，得到了PSB-19416（，12.6 nM）和PSB-18332（，2.98 nM）作为CD73的荧光高亲和力探针。预计这些化合物将成为生物学研究、药物筛选和诊断应用的有用工具。
