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J Med Chem. 2019 Apr 11;62(7):3677-3695. doi: 10.1021/acs.jmedchem.9b00164. Epub 2019 Mar 21.

Structure-Activity Relationship of Purine and Pyrimidine Nucleotides as Ecto-5'-Nucleotidase (CD73) Inhibitors.

Author information

1
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases , National Institutes of Health , Bethesda , Maryland 20892 , United States.
2
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I , University of Bonn , An der Immenburg 4 , D-53121 Bonn , Germany.
3
European Institute for Molecular Imaging (EIMI) , University of Münster , Waldeyerstr. 15 , D-48149 Münster , Germany.
4
Medicity Research Laboratory , University of Turku , 20520 Turku , Finland.
5
Department of Otorhinolaryngology-Head and Neck Surgery , Turku University Hospital and Turku University , 20520 Turku , Finland.
6
Institute for Pharmaceutical and Medicinal Chemistry , University of Münster , Correnstr. 48 , D-48149 Münster , Germany.
7
Institute of Cell Biology and Neuroscience , Goethe-University , D-60438 Frankfurt am Main , Germany.

Abstract

Cluster of differentiation 73 (CD73) converts adenosine 5'-monophosphate to immunosuppressive adenosine, and its inhibition was proposed as a new strategy for cancer treatment. We synthesized 5'- O-[(phosphonomethyl)phosphonic acid] derivatives of purine and pyrimidine nucleosides, which represent nucleoside diphosphate analogues, and compared their CD73 inhibitory potencies. In the adenine series, most ribose modifications and 1-deaza and 3-deaza were detrimental, but 7-deaza was tolerated. Uracil substitution with N3-methyl, but not larger groups, or 2-thio, was tolerated. 1,2-Diphosphono-ethyl modifications were not tolerated. N4-(Aryl)alkyloxy-cytosine derivatives, especially with bulky benzyloxy substituents, showed increased potency. Among the most potent inhibitors were the 5'- O-[(phosphonomethyl)phosphonic acid] derivatives of 5-fluorouridine (4l), N4-benzoyl-cytidine (7f), N4-[ O-(4-benzyloxy)]-cytidine (9h), and N4-[ O-(4-naphth-2-ylmethyloxy)]-cytidine (9e) ( Ki values 5-10 nM at human CD73). Selected compounds tested at the two uridine diphosphate-activated P2Y receptor subtypes showed high CD73 selectivity, especially those with large nucleobase substituents. These nucleotide analogues are among the most potent CD73 inhibitors reported and may be considered for development as parenteral drugs.

PMID:
30895781
PMCID:
PMC6526958
[Available on 2020-04-11]
DOI:
10.1021/acs.jmedchem.9b00164

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