A1 Refereed original research article in a scientific journal
Structure-Activity Relationship of Purine and Pyrimidine Nucleotides as Ecto-5 '-Nucleotidase (CD73) Inhibitors
Authors: Junker A., Renn C., Dobelmann C., Namasivayam V., Jain S., Losenkova K., Irjala H., Duca S., Balasubramanian R., Chakraborty S., Börgel F., Zimmermann H., Yegutkin G.G., Müller C.E., Jacobson K.A.
Publisher: AMER CHEMICAL SOC
Publication year: 2019
Journal: Journal of Medicinal Chemistry
Journal name in source: JOURNAL OF MEDICINAL CHEMISTRY
Journal acronym: J MED CHEM
Volume: 62
Issue: 7
First page : 3677
Last page: 3695
Number of pages: 19
ISSN: 0022-2623
DOI: https://doi.org/10.1021/acs.jmedchem.9b00164
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 N-3-methyl, but not larger groups, or 2-thio, was tolerated. 1,2-Diphosphono-ethyl modifications were not tolerated. N-4-(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 S-fluorouridine (41), N-4-benzoyl-cytidine (7f), N-4-[O-(4-benzyloxy)]-cytidine (9h), and N-4-[O-(4-naphth-2-ylmethyloxy)]-cytidine (9e) (K-i 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.
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 N-3-methyl, but not larger groups, or 2-thio, was tolerated. 1,2-Diphosphono-ethyl modifications were not tolerated. N-4-(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 S-fluorouridine (41), N-4-benzoyl-cytidine (7f), N-4-[O-(4-benzyloxy)]-cytidine (9h), and N-4-[O-(4-naphth-2-ylmethyloxy)]-cytidine (9e) (K-i 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.
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