29123-25-9

Upstream product

• 141-90-2 2-thiouracil 
• 3615-55-2 D-ribose 5-phosphate 
• 21052-18-6 2-thio-1-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-(3H)pyrimidine-2,4-dione 
• 20235-78-3 2-thiouridine 

Relevant academic research and scientific papers

Active site probes for yeast OMP decarboxylase: Inhibition constants of UMP and thio-substituted UMP analogues and greatly reduced activity toward CMP-6-carboxylate

The catalytic mechanism of orotidine-5'-monophosphate decarboxylase (ODCase, EC 4.1.1.23) involves a proton-sensitive step, probably proton donation to one of the carbonyl oxygens of the substrate, and may also include participation of a Zn2+ ion. To probe the active site for these mechanistic features, thio-substituted analogues of the product UMP were used as inhibitors of yeast ODCase. The intrinsic inhibition constants of the anionic pyrimidines were calculated using the measured inhibition constants and the pK(a) values of the respective compounds. 4-ThioUMP is a stronger inhibitor than UMP, while 2-thioUMP has a K(i) virtually the same as that for LIMP. A potential alternate substrate, CMP-6-carboxylate, has been synthesized and found to have undetectable activity and weak binding to ODCase. The results are discussed in a unified model for catalysis involving protonation at O2 and a proposed Zn2+ interaction at O4.

Human P2Y14 receptor agonists: Truncation of the hexose moiety of uridine-5′-diphosphoglucose and its replacement with alkyl and aryl groups

Uridine-5′-diphosphoglucose (UDPG) activates the P2Y14 receptor, a neuroimmune system GPCR. P2Y14 receptor tolerates glucose substitution with small alkyl or aryl groups or its truncation to uridine 5′-diphosphate (UDP), a full agonist at the human P2Y14 receptor expressed in HEK-293 cells. 2-Thiouracil derivatives displayed selectivity for activation of the human P2Y14 vs the P2Y6 receptor, such as 2-thio-UDP 4 (EC50=1.92 nMat P2Y14, 224-fold selectivity vs P2Y6) and its β-propyloxy ester 18. EC50 values of the β-methyl ester of UDP and its 2-thio analogue were 2730 and 56 nM, respectively. β-tert-Butyl ester of 4 was 11-fold more potent than UDPG, but β-aryloxy or larger, branched β-alkyl esters, such as cyclohexyl, were less potent. Ribose replacement of UDP with a rigid North or South methanocarba (bicyclo[3.1.0]hexane) group abolished P2Y14 receptor agonist activity. α,β-Methylene and difluoromethylene groups were well tolerated at the P2Y14 receptor and are expected to provide enhanced stability in biological systems. α,β-Methylene-2-thio-UDP 11 (EC50 = 0.92 nM) was 2160-fold selective versus P2Y6. Thus, these nucleotides and their congeners may serve as important pharmacological probes for the detection and characterization of the P2Y14 receptor.

Structure-activity relationship of uridine 5′-diphosphoglucose analogues as agonists of the human P2Y14 receptor

UDP-glucose (UDPG) and derivatives are naturally occurring agonists of the Gi protein-coupled P2Y14 receptor, which occurs in the immune system. We synthesized and characterized pharmacologically novel analogues of UDPG modified on the nucleobase, ribose, and glucose moieties, as the basis for designing novel ligands in conjunction with modeling. The recombinant human P2Y14 receptor expressed in COS-7 cells was coupled to phospholipase C through an engineered Gα-q/i protein. Most modifications of the uracil or ribose moieties abolished activity; this is among the least permissive P2Y receptors. However, a 2-thiouracil modification in 15 (EC50 49 ± 2 nM) enhanced the potency of UDPG (but not UDP-glucuronic acid) by 7-fold. 4-Thio analogue 13 was equipotent to UDPG, but S-alkylation was detrimental. Compound 15 was docked in a rhodposin-based receptor homology model, which correctly predicted potent agonism of UDP-fructose, UDP-mannose, and UDP-inositol. The hexose moiety of UDPG interacts with multiple H-bonding and charged residues and provides a fertile region for agonist modification.

Synthesis and structure-activity relationships of uracil nucleotide derivatives and analogues as agonists at human P2Y2, P2Y4, and P2Y6 receptors

A series of UTP, UDP, and UMP derivatives and analogues were synthesized and evaluated at the human pyrimidinergic P2Y receptor subtypes P2Y2, P2Y4, and P2Y6 stably expressed in 1321N1 astrocytoma cells. Substituents at N3