Design, synthesis and pharmacological evaluation of nucleotidic and non-nucleotidic inhibitors and probes for the ecto-5'-nucleotidase (CD73)

Abstract

Ecto-5'-nucleotidase (CD73) plays a central role in the metabolic breakdown of extracellular AMP. The enzyme is attached to the cell membrane by a glycosylphosphatidylinositol anchor, but can also be released by shedding, or integrated into exosomes. Overexpression of CD73 on cancer and immune cells leads to increased extracellular adenosine levels resulting in the activation of adenosine receptors (ARs). In the tumor microenvironment activation of ARs leads to an immunosuppressive, proliferation-enhancing, pro-angiogenic, and pro-metastatic environment. Several currently ongoing clincal studies evaluating monoclonal antibodies against CD73 and the first clinical studies employing a small-molecule CD73 inhibitor emphasize the clinical relevance of CD73 as a novel drug target. In this thesis, we describe the design, synthesis and pharmacological evaluation of CD73 inhibitors belonging to various scaffolds including α,β-methylene-adenosine diphosphates, diphosphonate mimetics, and xanthine derivatives. Furthermore, we describe the development of a fluorescent substrate, fluorescent probes, and further tool compounds for studying CD73. Whereas CD73 inhibitors could become a new class of immune-checkpoint inhibitory therapeutics, molecular probes have great potential as diagnostic tools and drugs.