6082-19-5Relevant articles and documents
Pyrimidine nucleotides containing a (S)-methanocarba ring as P2Y6 receptor agonists
Toti, Kiran S.,Jain, Shanu,Ciancetta, Antonella,Balasubramanian, Ramachandran,Chakraborty, Saibal,Surujdin, Ryan,Shi, Zhen-Dan,Jacobson, Kenneth A.
, p. 1897 - 1908 (2017)
Both agonists and antagonists of the UDP-activated P2Y6 receptor (P2Y6R) have been proposed for therapeutic use, in conditions such as cancer, inflammation, neurodegeneration and diabetes. Uracil nucleotides containing a south-bicyclo[3.1.0]hexane ((S)-methanocarba) ring system in place of the ribose ring were synthesized and shown to be potent P2Y6R agonists in a calcium mobilization assay. The (S)-methanocarba modification was compatible with either a 5-iodo or 4-methoxyimino group on the pyrimidine, but not with a α,β-methylene 5′-diphosphate. (S)-Methanocarba dinucleotide potency was compatible with a N4-methoxy modification on the proximal nucleoside that is assumed to bind at the P2Y6R similarly to UDP; (N)-methanocarba was preferred on the distal nucleoside moiety. This suggests that the distal dinucleotide P2Y6R binding site prefers a ribose-like group that can attain a (N) conformation, rather than (S). Dinucleotide binding was modeled by homology modeling, docking and molecular dynamics simulations, which suggested the same ribose conformational preferences found empirically.
Structure-Activity Relationship of Purine and Pyrimidine Nucleotides as Ecto-5′-Nucleotidase (CD73) Inhibitors
Junker, Anna,Renn, Christian,Dobelmann, Clemens,Namasivayam, Vigneshwaran,Jain, Shanu,Losenkova, Karolina,Irjala, Heikki,Duca, Sierra,Balasubramanian, Ramachandran,Chakraborty, Saibal,B?rgel, Frederik,Zimmermann, Herbert,Yegutkin, Gennady G.,Müller, Christa E.,Jacobson, Kenneth A.
, p. 3677 - 3695 (2019/03/29)
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.
N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO
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, (2016/07/27)
This disclosure relates to N4-hydroxycytidine derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to the treatment and prophylaxis of viral infections.