- Synthesis and structure-activity relationship of uracil nucleotide derivatives towards the identification of human P2Y6 receptor antagonists
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P2Y6 receptor (P2Y6-R) is involved in various physiological and pathophysiological events. With a view to set rules for the design of UDP-based reversible P2Y6-R antagonists as potential drugs, we established structure-activity relationship of UDP analogues, bearing modifications at the uracil ring, ribose moiety, and the phosphate chain. For instance, C5-phenyl- or 3-NMe-uridine-5′-α,β-methylene-diphosphonate, 16 and 23, or lack of 2′-OH, in 12-15, resulted in loss of both agonist and antagonist activity toward hP2Y6-R. However, uridylyl phosphosulfate, 19, selectively inhibited hP2Y6-R (IC50 112 μM) versus P2Y2/4-Rs. In summary, we have established a comprehensive SAR for hP2Y6-R ligands towards the development of hP2Y6-R antagonists.
- Meltzer, Diana,Ethan, Ophir,Arguin, Guillaume,Nadel, Yael,Danino, Ortal,Lecka, Joanna,Sévigny, Jean,Gendron, Fernand-Pierre,Fischer, Bilha
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supporting information
p. 5764 - 5773
(2015/11/11)
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- Pyrimidine nucleotides with 4-alkyloxyimino and terminal tetraphosphate δ-ester modifications as selective agonists of the P2Y4 receptor
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P2Y2 and P2Y4 receptors are G protein-coupled receptors, activated by UTP and dinucleoside tetraphosphates, which are difficult to distinguish pharmacologically for lack of potent and selective ligands. We structurally varied phosphate and uracil moieties in analogues of pyrimidine nucleoside 5′-triphosphates and 5′-tetraphosphate esters. P2Y4 receptor potency in phospholipase C stimulation in transfected 1321N1 human astrocytoma cells was enhanced in N4-alkyloxycytidine derivatives. OH groups on a terminal δ-glucose phosphoester of uridine 5′-tetraphosphate were inverted or substituted with H or F to probe H-bonding effects. N4-(Phenylpropoxy)-CTP 16 (MRS4062), Up 4-[1]3′-deoxy-3′-fluoroglucose 34 (MRS2927), and N 4-(phenylethoxy)-CTP 15 exhibit ≤10-fold selectivity for human P2Y4 over P2Y2 and P2Y6 receptors (EC 50 values 23, 62, and 73 nM, respectively). δ-3-Chlorophenyl phosphoester 21 of Up4 activated P2Y2 but not P2Y 4 receptor. Selected nucleotides tested for chemical and enzymatic stability were much more stable than UTP. Agonist docking at CXCR4-based P2Y2 and P2Y4 receptor models indicated greater steric tolerance of N4-phenylpropoxy group at P2Y4. Thus, distal structural changes modulate potency, selectivity, and stability of extended uridine tetraphosphate derivatives, and we report the first P2Y4 receptor-selective agonists.
- Maruoka, Hiroshi,Jayasekara, M. P. Suresh,Barrett, Matthew O.,Franklin, Derek A.,De Castro, Sonia,Kim, Nathaniel,Costanzi, Stefano,Harden, T. Kendall,Jacobson, Kenneth A.
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experimental part
p. 4018 - 4033
(2011/08/05)
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- Synthesis of AZT 5′-triphosphate mimics and their inhibitory effects on HIV-1 reverse transcriptase
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In search of active nucleoside 5′-triphosphate mimics, we have synthesized a series of AZT triphosphate mimics (AZT P3Ms) and evaluated their inhibitory effects on HIV-1 reverse transcriptase as well as their stability in fetal calf serum and in CEM cell
- Wang, Guangyi,Boyle, Nicholas,Chen, Fu,Rajappan, Vasanthakumar,Fagan, Patrick,Brooks, Jennifer L.,Hurd, Tiffany,Leeds, Janet M.,Rajwanshi, Vivek K.,Jin, Yi,Prhavc, Marija,Bruice, Thomas W.,Dan Cook
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p. 6902 - 6913
(2007/10/03)
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- Nucleotide mimics and their prodrugs
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The present invention relates to nucleoside diphosphate mimics and nucleoside triphosphate mimics, which contain diphosphate or triphosphate moiety mimics and optionally sugar-modifications and/or base-modifications. The nucleotide mimics of the present invention, in a form of a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutical formulation, are useful as antiviral, antimicrobial, and anticancer agents. The present invention provides a method for the treatment of viral infections, microbial infections, and proliferative disorders. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention optionally in combination with other pharmaceutically active agents.
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- Process for preparing methylene bisphosphonic and salts
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A process for the preparation of salts of substituted or unsubstituted methylene bisphosphonic acids by hydrolysing the corresponding acid ester with hydrochloric acid, removing water from the acid azeotropically prior to addition of an amine or a base to
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Page column 3-4
(2010/11/30)
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