ChemInform Abstract: THE SYNTHESIS AND METAL BINDING CHARACTERISTICS OF NOVEL, ISOPOLAR PHOSPHONATE ANALOGS OF NUCLEOTIDES

Blackburn, G. Michael; Kent, David E.; Kolkmann, Friedrich

doi:10.1002/chin.198434325

Cited by 5 publications

(8 citation statements)

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“…52,59 The smaller size of the β , γ -methylene group presumably allows tighter receptor binding than the larger β , γ -dihalomethylene group, consistent with the EC 50 values at the P2Y 1 R obtained for analogues 13 and 14 (Table 2). …”

Section: Discussionsupporting

confidence: 80%

“…Earlier, we reported that 2-MeS-β,γ-methylene-ATP was a potent and selective P2Y 1 receptor (P2Y 1 R) agonist. 27 Here, we examined whether a β,γ-dihalomethylene substitution in analogues 8-14 would enhance agonist potency at the P2Y 1 R due to the reduced pK a of the terminal phosphonate (∼7), as compared to the pK a of 8.4 52 for the corresponding methylene derivatives. Because analogues 8-14 should be 90% ionized under physiological conditions (vs 9% ionization for analogue 1), we expected that negatively charged phosphonates in analogues 8-14 would increase binding to the P2Y 1 R. Accordingly, the activities of analogues 8-14 were determined at the turkey P2Y 1 R heterologously expressed in human 1321N1 astrocytoma cells that are devoid of endogenous P2Y receptors.…”

Section: Resultsmentioning

confidence: 99%

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2-MeS-β,γ-CCl₂-ATP is a Potent Agent for Reducing Intraocular Pressure

et al. 2010

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Extracellular nucleotides can modify the production or drainage of the aqueous humor via activation of P2 receptors and therefore affect the intraocular pressure (IOP). We have synthesized slowly hydrolyzable nucleoside di- and triphosphate analogues, 1, and 8–14. Analogues 8–14 were completely resistant to hydrolysis by alkaline phosphatase over 30 min at 37 °C. In human blood serum, analogues 8–14 exhibited high stability, e.g., analogues 9 and 10–14 were only 15% and 0% degraded after 24 h, respectively. Moreover, analogues 8–14 were highly stable at pH 1.4 (t1/21 h–30 days). Analogues 8–14 were agonists of the P2Y1 receptor (EC50 0.57–9.54μM). Ocular administration of most analogues into rabbits reduced IOP, e.g., analogue 9 reduced IOP by 32% (EC50 95.5 nM). Analogue 9 was more effective at reducing IOP than several common glaucoma drugs and represents a promising alternative to timolol maleate, which cannot be used for the treatment of patients suffering from asthma or cardiac problems.

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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

2-MeS-β,γ-CCl₂-ATP is a Potent Agent for Reducing Intraocular Pressure

et al. 2010

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“…The ss-siRNA 63 containing 5′- trans -fluorovinylphosphonate (( E )-5′-F-VP) modification showed higher potency (IC 50 7 nM; Figure 13 ) relative to 5′- cis -vinylphosphonate (( Z )-5′-VP) 64 (IC 50 40 nM; Figure 13 ). It is surprising that ss-siRNA 63 was 7-fold less potent than ss-siRNA 61 given that fluorination of the alpha carbon of the 5′-VP modification ( 38 , 39 ) was expected to be isoelectronic compared to the phosphate. These data demonstrate that the factors other than electronics are contributing to the activity of ( E )-5′-VP ss-siRNA.…”

Section: Resultsmentioning

confidence: 99%

Identification of metabolically stable 5′-phosphate analogs that support single-stranded siRNA activity

Prakash

Lima

Murray

et al. 2015

Nucleic Acids Research

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The ss-siRNA activity in vivo requires a metabolically stable 5′-phosphate analog. In this report we used crystal structure of the 5′-phosphate binding pocket of Ago-2 bound with guide strand to design and synthesize ss-siRNAs containing various 5′-phosphate analogs. Our results indicate that the electronic and spatial orientation of the 5′-phosphate analog was critical for ss-siRNA activity. Chemically modified ss-siRNA targeting human apoC III mRNA demonstrated good potency for inhibiting ApoC III mRNA and protein in transgenic mice. Moreover, ApoC III ss-siRNAs were able to reduce the triglyceride and LDL cholesterol in transgenic mice demonstrating pharmacological effect of ss-siRNA. Our study provides guidance to develop surrogate phosphate analog for ss-siRNA and demonstrates that ss-siRNA provides an alternative strategy for therapeutic gene silencing.

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“…Moreover, published 13 P NMR data for diphosphate analogues bearing a β,γ-methylene bridge substituted with bulky and anionic functions did not shown an increase of the 2 Jβγ coupling constant. 34 This unusual degree of electronic interaction between β and γ the phosphorus atoms, previously reported in other series for difluoromethylene diphosphate analogues, 35 – 37 reflects a complex set factors including the combined electronegativity and dπ-bonding possibilities for a β-P ligand which may led to conformational changes in the phosphoryl chain. 35 …”

Section: Discussionmentioning

confidence: 59%

Synthesis and substrate properties towards HIV-1 reverse transcriptase of new diphosphate analogues of 9-[(2-phosphonomethoxy)ethyl]adenine

Laux

Priet²,

Alvarez³

et al. 2018

Antivir Chem Chemother

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BackgroundThe replacement of β,γ-pyrophosphate by β,γ-phosphonate moieties within the triphosphate chain of 5′-triphosphate nucleoside analogues was previously studied for various antiviral nucleoside analogues such as AZT and 2′,3′-dideoxynucleosides. Thus, it has been shown that these chemical modifications could preserve, in some cases, the terminating substrate properties of the triphosphate analogue for HIV-RT. Herein, we aimed to study such 5′-triphosphate mimics based on the scaffold of the well-known antiviral agent 9-[(2-phosphonomethoxy)ethyl]adenine (PMEA, Adefovir).MethodsSynthesis involved coupling of a morpholidate derivative of PMEA with appropriate pyrophosphoryl analogues. The relative efficiencies of incorporation of the studied diphosphate phosphonates were measured using subtype B WT HIV-1 RT in an in vitro susceptibility assay, in comparison to the parent nucleotide analogue (PMEApp).ResultsSearching for nucleoside 5′-triphosphate mimics, we have synthesized and studied a series of diphosphate analogues of PMEA bearing non hydrolysable bonds between the and phosphorus atoms. We also examined their relative inhibitory capacity towards HIV-1 reverse transcriptase in comparison to the parent nucleotide analogue (PMEApp). Only one of them appeared as a weak inhibitor (IC50 = 403.0 ± 75.5 µM) and proved to be less effective than PMEApp (IC50 = 6.4 ± 0.8 µM).ConclusionPMEA diphosphoryl derivatives were designed as potential substrates and/or inhibitors of various viral polymerases. These modifications dramatically affect their ability to inhibit HIV-RT.

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ChemInform Abstract: THE SYNTHESIS AND METAL BINDING CHARACTERISTICS OF NOVEL, ISOPOLAR PHOSPHONATE ANALOGS OF NUCLEOTIDES

Cited by 5 publications

References 1 publication

2-MeS-β,γ-CCl₂-ATP is a Potent Agent for Reducing Intraocular Pressure

2-MeS-β,γ-CCl₂-ATP is a Potent Agent for Reducing Intraocular Pressure

Identification of metabolically stable 5′-phosphate analogs that support single-stranded siRNA activity

Synthesis and substrate properties towards HIV-1 reverse transcriptase of new diphosphate analogues of 9-[(2-phosphonomethoxy)ethyl]adenine

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ChemInform Abstract: THE SYNTHESIS AND METAL BINDING CHARACTERISTICS OF NOVEL, ISOPOLAR PHOSPHONATE ANALOGS OF NUCLEOTIDES

Cited by 5 publications

References 1 publication

2-MeS-β,γ-CCl2-ATP is a Potent Agent for Reducing Intraocular Pressure

2-MeS-β,γ-CCl2-ATP is a Potent Agent for Reducing Intraocular Pressure

Identification of metabolically stable 5′-phosphate analogs that support single-stranded siRNA activity

Synthesis and substrate properties towards HIV-1 reverse transcriptase of new diphosphate analogues of 9-[(2-phosphonomethoxy)ethyl]adenine

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2-MeS-β,γ-CCl₂-ATP is a Potent Agent for Reducing Intraocular Pressure

2-MeS-β,γ-CCl₂-ATP is a Potent Agent for Reducing Intraocular Pressure