Inhibition of DNA synthesis in Escherichia coli by 1-(β-D-ribofuranosyl)-2-pyrimidone

Votruba, Ivan; Holý, Antonı́n; Pischel, H.

doi:10.1135/cccc19722213

Cited by 7 publications

(3 citation statements)

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“…An interesting "double prodrug" is pyrimidin-2-one beta-D-ribofuranoside (zebularine, 5) [22] that, in contrast to the base (6) or to its 2-deoxyriboside (7), can cross the bacterial cell wall and release the base into the cytosol. The base is then converted to the 2 0 -deoxyribonucleotide (8, 4-deoxy derivative of dUMP or 4-desamino analog of dCMP), which is an efficient substrate/inhibitor of the bacterial thymidylate synthase.…”

Section: Sar In the First Generation Of Antimetabolitesmentioning

confidence: 99%

Anti‐DNAVirus Agents

Holý

Clercq

2010

Burger's Medicinal Chemistry and Drug Discovery

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Anti‐DNA virus agents that are inhibitory to the replication of DNA viruses have been reviewed by Tim Middleton and Rockway in Burger's Medicinal Chemistry, 6th ed., volume 5. Here we will address the various agents effective against these different viruses. For each of the (classes of) compound(s), we will, where applicable, specifically focus on (i) the antiviral compounds that are clinically available; (ii) the antiviral compounds that are under (pre)clinical development; (iii) the mechanism of action of the compounds; (iv) their structure–activity relationship (SAR); (v) resistance that may have arisen; (vi) recent clinical data obtained with the compounds while under development. Previous reviews on antiviral agents have been dealing with “looking back in 2009 at the dawning of antiviral therapy now 50 years ago: an historical perspective,” highlighting the discovery of acyclovir [9‐(2‐hydroxyethoxymethyl)guanine] as a specific antiherpetic agent, “the design of drugs for HIV and HCV,” “HIV drug development: the next 25 years,” “interferons at age 50: past, current, and future impact on biomedicine,” “the way forward in HCV treatment‐finding the right path,” “antiviral treatment of chronic hepatitis B virus infections: the past, the present, and the future,” “antiviral agents active against influenza A viruses,” “the war against influenza: discovery and development of sialidase inhibitors,” “antivirals and antiviral strategies,” and “clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections.”

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Section: Sar In the First Generation Of Antimetabolitesmentioning

confidence: 99%

Anti‐DNAVirus Agents

Holý

Clercq

2010

Burger's Medicinal Chemistry and Drug Discovery

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“…The family of 2-pyrimidinone nucleosides plays an important role among biologically active analogues of natural pyrimidine nucleosides and was intensively investigated. Parent 1-β-D-ribofuranosylpyrimidin-2-one (zebularine, zeb) exhibits an antibacterial activity connected with its in vivo transformation into 1-(2′-deoxy-β-D-ribofuranosyl)pyrimidin-2-one 5′-phosphate, a strong inhibitor of thymidylate synthetase 2,3 . Zebularine is also a strong cytidine deaminase inhibitor 4,5 and effectively inhibits DNA methylation 6,7 .…”

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confidence: 99%

2-Thiozebularine: base modified nucleoside fully constrained in C3′-endo conformation in solution

Ebenryter

Jankowski

Karolak‐Wojciechowska

et al. 2011

Collect. Czech. Chem. Commun.

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This article is dedicated to Professor Antonín Holý on the occasion of his 75th birthday in recognition of his outstanding contribution to the area of nucleic acids chemistry.2-Thiopyrimidinone ribofuranoside (2-thiozebularine, s 2 zeb) was synthesized by the adaptation of silyl method of N-glycosidic bond formation and using thionation of protected 2-oxonucleoside derivative (zebularine, zeb) with Lawesson reagent. The X-ray crystal structure of s 2 zeb and NMR determined conformations of s 2 zeb and zeb in solution were compared with structures of 2-thiouridine (s 2 U) and uridine (U). In the solid state s 2 zeb molecule adopts conformation typical for ribonucleosides: C3′-endo C2′-exo twist type of ribofuranose pucker, anti of N-glycosidic bond and trans around C4′-C5′ bond. In aqueous solution, however, almost 100% population of s 2 zeb exhibits C3′-endo ribofuranose pucker. The population of N-conformer of s 2 zeb is about 20% higher than for zeb (analogously to pair of s 2 U and U nucleosides) indicating similar influence of steric effect of bulky sulfur atom on stabilization of N-type ribose conformation. Interestingly, the absence of 4-carbonyl function in zeb and s 2 zeb raises the population of C3′-endo conformation by about 30% in comparison to U and s 2 U as a result of significant anomeric effect. Additive action of both effects makes the 2-thiozebularine almost fully constrained in C3′-endo conformation in aqueous solution. Cytotoxic properties of s 2 zeb are less pronounced in comparison to zebularine, with IC 50 > 100 mM for HeLa and K562 cancer cells and for HUVEC non-cancerous cells.

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“…ty. Oyen (3) and Holy and co-workers (4) showed that 1-(p-D-ribofuranosy1)-2-pyrimidinone is an efficient inhibitor of DNA synthesis in E. coli, and the latter group subsequently studied a number of other synthetic nucleosides derived from 1 (5). McCormack et al (6) have recently reported that 2-pyrimidinone riboside and related compounds are inhibitors of the enzyme cytidine deaminase, and 5-halo derivatives of 1 are reported (7) to have potential value as metaphase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

The mass spectra of pyrimidines: 2(1H)-pyrimidinone and some N(1)-substituted derivatives

Rye¹,

Tee²,

Kazdan³

1982

Can. J. Chem.

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The EI induced fragmentation of 2-pyrimidinone (1) and several N(1)-substituted derivatives has been studied. Principal fragmentation pathways have been identified using 2H labelling, metastable defocussing, and exact mass measurements.The fragmentation of 1 parallels that of cytosine. The hydrogen atom at C(4), and not the tautomeric hydrogen, is involved in the formation of the prominent [M – H]+ peak in the spectrum of 1; subsequent fragmentations of the [M – H]+ moiety contribute significantly to the spectrum.Side chain eliminations predominate in the mass spectra of the N(1)-substituted derivatives, but peaks characteristic of the pyrimidinone nucleus are observable in every case. Alternative structures for the [M – H]+ entity formed by H• loss from the substituent are proposed for the N-phenyl and N-benzyl compounds.

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Inhibition of DNA synthesis in Escherichia coli by 1-(β-D-ribofuranosyl)-2-pyrimidone

Cited by 7 publications

References 0 publications

Anti‐DNAVirus Agents

Anti‐DNAVirus Agents

2-Thiozebularine: base modified nucleoside fully constrained in C3′-endo conformation in solution

The mass spectra of pyrimidines: 2(1H)-pyrimidinone and some N(1)-substituted derivatives

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