Structure-activity relationships of pyrimidine nucleotides containing a 5′-α,β-methylene diphosphonate at the P2Y6 receptor

Oliva, Paola; Scortichini, Mirko; Dobelmann, Clemens; Jain, Shanu; Gopinatth, Varun; Toti, Kiran S.; Phung, Ngan B.; Junker, Anna; Jacobson, Kenneth A.

doi:10.1016/j.bmcl.2021.128137

Cited by 8 publications

(6 citation statements)

References 44 publications

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“…Compounds 1–3 , 9 , 75 , and 76 (Table ) were prepared as previously reported. − As shown in Scheme , synthesis of compounds 10–21 required the preparation of various aryl-substituted benzyloxyamines ( 32–43 ). These benzyloxyamines were produced following the previously reported procedure, , starting from the corresponding substituted benzyl bromides. Similar methods were used to prepare phenylethyl and phenylpropyl homologues (structures not shown) of the benzyl derivatives.…”

Section: Resultsmentioning

confidence: 99%

“…O-3-(Trifluoromethyl)benzylhydroxylamine Hydrochloride (34). The product was obtained as a white solid (130 mg) in 68% yield: 1 H NMR (MeOD, 400 Hz) δ 7.61−7.78 (m, 4H), 5.12 (s, 2H).…”

Section: ■ Conclusionmentioning

confidence: 99%

“…We recently extended this approach by replacing the adenine-like nucleobase entirely, in pyrimidine 5′-nucleoside 3-methylcytidine-5′-α,β-methylenediphosphonate derivatives, such as compound 9 . The cytidine 3-methyl group that is common to these potent inhibitors was shown previousy to completely block affinity at the UDP-selective P2Y 6 receptor . These N 4 -substituted 3-methylcytidine-5′-α,β-methylenediphosphonates do not produce adenosine derivatives as nucleoside metabolites, i.e., making AR activation less likely.…”

Section: Introductionmentioning

confidence: 99%

“…28 The cytidine 3-methyl group that is common to these potent inhibitors was shown previousy to completely block affinity at the UDP-selective P2Y 6 receptor. 34 These N 4 -substituted 3-methylcytidine-5′-α,β-methylenediphosphonates do not produce adenosine derivatives as nucleoside metabolites, i.e., making AR activation less likely. We now further explore the structure−activity relationship (SAR) of these pyrimidine nucleotides as inhibitors of human (h) CD73.…”

Section: ■ Introductionmentioning

confidence: 99%

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Structure–Activity Relationship of 3-Methylcytidine-5′-α,β-methylenediphosphates as CD73 Inhibitors

et al. 2022

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We recently reported N 4-substituted 3-methylcytidine-5′-α,β-methylenediphosphates as CD73 inhibitors, potentially useful in cancer immunotherapy. We now expand the structure–activity relationship of pyrimidine nucleotides as human CD73 inhibitors. 4-Chloro (MRS4598 16; K i = 0.673 nM) and 4-iodo (MRS4620 18; K i = 0.436 nM) substitution of the N 4-benzyloxy group decreased K i by ∼20-fold. Primary alkylamine derivatives coupled through a p-amido group with a varying methylene chain length (24 and 25) were functionalized congeners, for subsequent conjugation to carrier or reporter moieties. X-ray structures of hCD73 with two inhibitors indicated a ribose ring conformational adaptation, and the benzyloxyimino group (E configuration) binds to the same region (between the C-terminal and N-terminal domains) as N 4-benzyl groups in adenine inhibitors. Molecular dynamics identified stabilizing interactions and predicted conformational diversity. Thus, by N 4-benzyloxy substitution, we have greatly enhanced the inhibitory potency and added functionality enabling molecular probes. Their potential as anticancer drugs was confirmed by blocking CD73 activity in tumor tissues in situ.

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Section: Resultsmentioning

confidence: 99%

“…O-3-(Trifluoromethyl)benzylhydroxylamine Hydrochloride (34). The product was obtained as a white solid (130 mg) in 68% yield: 1 H NMR (MeOD, 400 Hz) δ 7.61−7.78 (m, 4H), 5.12 (s, 2H).…”

Section: ■ Conclusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Structure–Activity Relationship of 3-Methylcytidine-5′-α,β-methylenediphosphates as CD73 Inhibitors

et al. 2022

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“…Future studies using liver-specific KO mouse models for understanding liver diseases are warranted. Numerous potent ligands for purinergic receptors have been synthesized that can be tested in preclinical mouse models of liver diseases (96)(97)(98)(99)(100)(101)(102)(103). Characterization of agonists and antagonists for purinergic receptors in preclinical mouse models may foster the development of novel drugs for the treatment of liver diseases.…”

Section: Discussionmentioning

confidence: 99%

Purinergic Signaling in Liver Pathophysiology

Jain

Jacobson

2021

Front. Endocrinol.

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Extracellular nucleosides and nucleotides activate a group of G protein-coupled receptors (GPCRs) known as purinergic receptors, comprising adenosine and P2Y receptors. Furthermore, purinergic P2X ion channels are activated by ATP. These receptors are expressed in liver resident cells and play a critical role in maintaining liver function. In the normal physiology, these receptors regulate hepatic metabolic processes such as insulin responsiveness, glycogen and lipid metabolism, and bile secretion. In disease states, ATP and other nucleotides serve as danger signals and modulate purinergic responses in the cells. Recent studies have demonstrated that purinergic receptors play a significant role in the development of metabolic syndrome associated non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, hepatocellular carcinoma (HCC) and liver inflammation. In this concise review, we dissect the role of purinergic signaling in different liver resident cells involved in maintaining healthy liver function and in the development of the above-mentioned liver pathologies. Moreover, we discuss potential therapeutic strategies for liver diseases by targeting adenosine, P2Y and P2X receptors.

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Moving out of CF₃‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF₅) Group

Witoszka,

Matalińska,

Misicka

et al. 2023

ChemMedChem

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The NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including i.a. emesis, pain or cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF3 groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF5‐group, and so we designed, synthesized and tested for NK1R affinity ten novel SF5‐containing compounds. All the novel analogues exhibit detectable NK1R binding, with the best of them, compound 5a, binding only slightly worse (IC50 = 34.3 nM) than the approved NK1R‐targeting drug, aprepitant (IC50 = 27.7 nM). Molecular docking provided structural explanation of SAR. According to our analysis, the SF5 group in our compounds occupies a position similar to that of one of CF3 groups of aprepitant as found in the crystal structure. Additionally, we checked on whether the docking scoring function or energies derived from Fragment Molecular Orbital quantum chemical calculations may be helpful in explaining and predicting the experimental receptor affinities for our analogues. Both these methods produce moderately good results. Overall, this is the first demonstration of the utility of the SF5‐group in the design of NK1R ligands.

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Structure-activity relationships of pyrimidine nucleotides containing a 5′-α,β-methylene diphosphonate at the P2Y6 receptor

Cited by 8 publications

References 44 publications

Structure–Activity Relationship of 3-Methylcytidine-5′-α,β-methylenediphosphates as CD73 Inhibitors

Structure–Activity Relationship of 3-Methylcytidine-5′-α,β-methylenediphosphates as CD73 Inhibitors

Purinergic Signaling in Liver Pathophysiology

Moving out of CF₃‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF₅) Group

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Structure-activity relationships of pyrimidine nucleotides containing a 5′-α,β-methylene diphosphonate at the P2Y6 receptor

Cited by 8 publications

References 44 publications

Structure–Activity Relationship of 3-Methylcytidine-5′-α,β-methylenediphosphates as CD73 Inhibitors

Structure–Activity Relationship of 3-Methylcytidine-5′-α,β-methylenediphosphates as CD73 Inhibitors

Purinergic Signaling in Liver Pathophysiology

Moving out of CF3‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF5) Group

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Product

Resources

About

Moving out of CF₃‐Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF₅) Group