Nucleobase Protection of Deoxyribo‐ and Ribonucleosides

Meher, Geeta; Meher, Nabin K.; Iyer, Radhakrishnan P.

doi:10.1002/0471142700.nc0201s00

Cited by 2 publications

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References 131 publications

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“…The only nucleotide-based RSH inhibitor that showed activity against bacterial cultures, Relacin, has N 2 -isobutyryl-guanine (G iBu ) modification of the nucleotide base 25 . This modification is a common protective group used in nucleotide chemistry 30 . The original publication did not explain the rationale behind using this modification – Is it important for the SAR of the inhibitor?…”

Section: Resultsmentioning

confidence: 99%

Molecular mutagenesis of ppGpp: turning a RelA activator into an inhibitor

Beljantseva

Kudrin

Jimmy

et al. 2017

Sci Rep

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The alarmone nucleotide (p)ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance and virulence, making (p)ppGpp-mediated signaling a promising target for development of antibacterials. Although ppGpp itself is an activator of the ribosome-associated ppGpp synthetase RelA, several ppGpp mimics have been developed as RelA inhibitors. However promising, the currently available ppGpp mimics are relatively inefficient, with IC50 in the sub-mM range. In an attempt to identify a potent and specific inhibitor of RelA capable of abrogating (p)ppGpp production in live bacterial cells, we have tested a targeted nucleotide library using a biochemical test system comprised of purified Escherichia coli components. While none of the compounds fulfilled this aim, the screen has yielded several potentially useful molecular tools for biochemical and structural work.

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Section: Resultsmentioning

confidence: 99%

Molecular mutagenesis of ppGpp: turning a RelA activator into an inhibitor

Beljantseva

Kudrin

Jimmy

et al. 2017

Sci Rep

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“…Amino protection of adenosine with the benzoyl group and guanosine with the isobutyryl group can be carried out by the same transient protection procedure (Fan, Gaffeny, & Jones, 2004; Ti, Gaffney, & Jones,1982), and these derivatives are more easily handled than are the more‐labile phenoxyacetylated compounds. A general discussion of amino‐protecting groups and literature references is given in Current Protocols article Iyer (2001).…”

Section: Commentarymentioning

confidence: 99%

Regioselective 2′‐Silylation of Purine Ribonucleosides for Phosphoramidite RNA Synthesis

Gaffney

Jones

2023

Current Protocols

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This unit describes high-yield procedures for protection of purine ribonucleosides based on a reaction that allows highly regioselective 2′-silylation. The H-phosphonate monoester group produced in the silylation reaction is then cleaved, without silyl migration (Song et al., 1999;Zhang et al., 1997), to give intermediates ready for phosphitylation to yield the phosphoramidites. This method gives overall yields that are three times the best yields available by conventional procedures for adenosine (see Basic Protocol 1) and guanosine (see Basic Protocol 2), but offers no advantage for cytidine or uridine. BASIC PROTOCOL 1 SYNTHESIS OF 5′-O-(4,4′-DIMETHOXYTRITYL)-2′-O-tert-BUTYLDIMETHYLSILYL-6-N-ACYLADENOSINEThis protocol makes use of transient protection of the 2′,3′-diol moiety of a ribonucleoside (S.2 in Fig. 2.8.1) by reaction with N,N-dimethylformamide dimethylacetal (Zemlicka, 1963) to prevent the small, but potentially troublesome, tritylation of the 2′-hydroxyl that otherwise accompanies tritylation of the 5′-hydroxyl (Zhang et al., 1997). The 2′,3′-Odimethylaminomethylene group is cleaved by any protic solvent. The N-dimethylaminomethylene group is cleaved by treatment with either aqueous ammonia or methylamine. The phenoxyacetylation reaction is carried out using the hydroxybenzotriazole active ester of phenoxyacetic acid after transient hydroxyl protection with trimethylchlorosilane.The regioselective silylation of the N-and 5′-O-protected adenosine and guanosine derivatives (S.4 and S.13, respectively) presumably occurs by a reaction sequence in which the phenyl-H-phosphonate reacts first with tert-butyldimethylchlorosilane to generate the corresponding diester, which then undergoes a transesterification with S.4/S.13 to generate a mixture of isomers (S.5/S.14). Subsequent transfer of the tert-butyldimethylsilyl (TBDMS) group predominantly to the more acidic 2′-hydroxyl gives S.6a/S15a along with 10% to 15% of the 3′-O-TBDMS isomers. The H-phosphonate moiety is removed by reaction of the isomers of S.6a,b/S15a,b with ethylene glycol or glycerol. The extraordinarily facile transesterification of H-phosphonate diesters in the presence of a vicinal hydroxyl group effects the conversion to S.8a,b/S.17a,b quantitatively within minutes, presumably via the intermediate S.7a,b/S.16a,b.After careful purification, S8a/S.17a are converted to the phosphoramidites S.9/S.18 by reaction with 2-cyanoethyl tetraisopropylphosphorodiamidite using diisopropylammonium tetrazolide as a catalyst. A short silica gel column removes the excess reagent.For H-phosphonate synthesis, monomers like S.6a/S.15a but without amino protection can be prepared by a similar route (Zhang et al., 1997). The labile phenoxyacetyl group used here does not survive the polar conditions required for purification of the charged H-phosphonates.

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Nucleobase Protection of Deoxyribo‐ and Ribonucleosides

Cited by 2 publications

References 131 publications

Molecular mutagenesis of ppGpp: turning a RelA activator into an inhibitor

Molecular mutagenesis of ppGpp: turning a RelA activator into an inhibitor

Regioselective 2′‐Silylation of Purine Ribonucleosides for Phosphoramidite RNA Synthesis

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