Fluorescent Probes for Ecto-5'-nucleotidase (CD73)

Constanze C Schmies; Georg Rolshoven; Riham M Idris; Karolina Losenkova; Christian Renn; Laura Schäkel; Haneen Al-Hroub; Yulu Wang; Francesca Garofano; Ingo G H Schmidt-Wolf; Herbert Zimmermann; Gennady G Yegutkin; Christa E Müller

doi:10.1021/acsmedchemlett.0c00391

Fluorescent Probes for Ecto-5'-nucleotidase (CD73)

ACS Med Chem Lett. 2020 Sep 3;11(11):2253-2260. doi: 10.1021/acsmedchemlett.0c00391. eCollection 2020 Nov 12.

Affiliations

¹ PharmaCenter Bonn, Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
² MediCity Research Laboratory, University of Turku, 20520 Turku, Finland.
³ Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital Bonn, Bonn D-53127, Germany.
⁴ Institute of Cell Biology and Neuroscience, Goethe-University, D-60438 Frankfurt am Main, Germany.

Abstract

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 N ⁶ -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 (14b, K _i 12.6 nM) and PSB-18332 (14a, K _i 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.