Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation

Parmenopoulou, Vanessa; Chatzileontiadou, D.S.M.; Manta, Stella; Bougiatioti, Stamatina; Maragozidis, Panagiotis; Gkaragkouni, Dimitra Niki; Kaffesaki, Eleni; Kantsadi, A.L.; Skamnaki, Vassiliki T.; Zographos, S.E.; Zounpoulakis, Panagiotis; Balatsos, Nikolaos A. A.; Komiotis, Dimitris; Leonidas, D.D.

doi:10.1016/j.bmc.2012.09.067

Cited by 27 publications

(17 citation statements)

References 37 publications

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“…The in vivo inhibitory potencyp attern of these compounds does not seem to follow their enzymatic inhibitory potency in RNase A. [21] However,t he most potent compound, 4a, with a K i value of 1.6 mm for RNase A( Ta ble 1), completely inhibits the biological activity of Pyr1-hAng in the CAM assay. The presence of the triazole group seems to significantly influence the antiangiogenic potency.T hus, in general, 1,2,3-triazole 5-substitutedu racil furanonucleosides 4a-e are more potent than the C5-substituted uridines 6a-e.H owever,C 5 substituents Ha nd Br seem to increase the inhibitory potency regardless of the presence of the triazole linker,a sr ibofuranosyl pyrimidine nucleosides 6a and 6c and their corresponding 1,2,3-triazole derivatives 4a and 4c,b earing, respectively,t he same group at the C5 position, inhibit Pyr1-hAng activity to the same extent.…”

Section: Resultsmentioning

confidence: 97%

“…Therefore, it seems that the inhibitory effect is dose dependent. The in vivo inhibitory potency pattern of these compounds does not seem to follow their enzymatic inhibitory potency in RNase A . However, the most potent compound, 4 a , with a K i value of 1.6 μ m for RNase A (Table ), completely inhibits the biological activity of Pyr1‐hAng in the CAM assay.…”

Section: Resultsmentioning

confidence: 98%

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Evidence for Novel Action at the Cell‐Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy, in silico and in vivo Studies

et al. 2018

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A member of the ribonuclease A superfamily, human angiogenin (hAng) is a potent angiogenic factor. Heteronuclear NMR spectroscopy combined with induced-fit docking revealed a dual binding mode for the most antiangiogenic compound of a series of ribofuranosyl pyrimidine nucleosides that strongly inhibit hAng's angiogenic activity in vivo. While modeling suggests the potential for simultaneous binding of the inhibitors at the active and cell-binding sites, NMR studies indicate greater affinity for the cell-binding site than for the active site. Additionally, molecular dynamics simulations at 100 ns confirmed the stability of binding at the cell-binding site with the predicted protein-ligand interactions, in excellent agreement with the NMR data. This is the first time that a nucleoside inhibitor is reported to completely inhibit the angiogenic activity of hAng in vivo by exerting dual inhibitory activity on hAng, blocking both the entrance of hAng into the cell and its ribonucleolytic activity.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 98%

Evidence for Novel Action at the Cell‐Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy, in silico and in vivo Studies

et al. 2018

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“…Pyrimidine nucleoside analogues in which a 1,2,3-triazole ring was attached either directly to the C5 position of 2′-deoxyuridine or via a methylene unit were synthesized and exhibited both antiviral activity against herpes simplex viruses, varicella-zoster virus, human cytomegalovirus, vaccinia virus [28][29][30][31] and significant anticancer effects against cancer cell lines PC-3, MDA-MB-231, ACHN [28]. Recently, a series of nucleoside analogues in which the pyrimidine fragment was attached to the ribose moiety at the C1′ carbon via a 1,2,3-triazolyl bridge has been synthesized [32][33][34][35]. No inhibitory activity against HCV virus was observed with any of these compounds, but several C5-substituted 1-β-dribofuranosyl-1,2,3-triazolidomethyluracils showed potent inhibitory activity against RNase A [34] and completely inhibited the angiogenic activity of hAng in vivo [35].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity

et al. 2020

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Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4-yl moiety by a polymethylene linker of variable length. Target compounds were prepared by the Cu alkyne-azide cycloaddition (CuAAC) reaction. Derivatives of uracil, 6-methyluracil, 3,6-dimethyluracil, thymine and quinazolin-2,4-dione with ω-alkyne substituent at the N1 (or N5) atom and azido 2,3,5-triO -acetyl-D-β-ribofuranoside were used as components of the CuAAC reaction. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. The best values of IC 50 (inhibiting concentration) and SI (selectivity index) were demonstrated by the lead compound 4i in which the 1,2,3-triazolylribofuranosyl fragment is attached to the N1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC 50 = 30 μM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N5 atom of the 6-methyluracil moiety (IC 50 = 15 μM, SI = 5). According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 4i and 8n against H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRP).

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“…Monopropargyl pyrimidine nucleobases (uracil and thymine) are versatile building blocks for the synthesis of biologically relevant 1,2,3-triazoles [11]. They are generally used as starting material for the synthesis of triazole nucleosides [12][13][14][15][16][17][18][19], triazole nucleotides [20][21][22][23], oxiconazole analogues [24], nucleopeptides [25], inhibitors of human topoisomerase type II [26], and nucleoamino oxyacids [27]. Further, these propargyl nucleobases are also used in the synthesis of organogels [28], and as corrosion inhibitors [29].…”

Section: Introductionmentioning

confidence: 99%

Multicomponent Click Synthesis of New 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases: Promising Acidic Corrosion Inhibitors for Steel

et al. 2013

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A series of new mono-1,2,3-triazole derivatives of pyrimidine nucleobases were synthesized by one-pot copper(I)-catalyzed 1,3-dipolar cycloaddition reactions between N-1-propargyluracil and thymine, sodium azide and several benzyl halides. The desired heterocyclic compounds were obtained in good yields and characterized by NMR, IR, and high resolution mass spectrometry. These compounds were investigated as corrosion inhibitors for steel in 1 M HCl solution, using electrochemical impedance spectroscopy (EIS) technique. The results indicate that these heterocyclic compounds are promising acidic corrosion inhibitors for steel.

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Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation

Cited by 27 publications

References 37 publications

Evidence for Novel Action at the Cell‐Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy, in silico and in vivo Studies

Evidence for Novel Action at the Cell‐Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy, in silico and in vivo Studies

Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity

Multicomponent Click Synthesis of New 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases: Promising Acidic Corrosion Inhibitors for Steel

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