Bromination of nucleosides

Srivastava, P. C.; Nagpal, K. L.

doi:10.1007/bf01895597

Cited by 19 publications

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“…The N 7 -substituted 8-MG analogues were prepared via alkylation of 8-bromo-N 2 -acetylguanine ( 18 ), formed in two steps from guanosine ( 16 ) according to a literature method [32], [33] (Fig. 4).…”

Section: Resultsmentioning

confidence: 99%

Exploring the Chemical Space around 8-Mercaptoguanine as a Route to New Inhibitors of the Folate Biosynthesis Enzyme HPPK

et al. 2013

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As the second essential enzyme of the folate biosynthetic pathway, the potential antimicrobial target, HPPK (6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase), catalyzes the Mg2+-dependant transfer of pyrophosphate from the cofactor (ATP) to the substrate, 6-hydroxymethyl-7,8-dihydropterin. Recently, we showed that 8-mercaptoguanine (8-MG) bound at the substrate site (KD ∼13 µM), inhibited the S. aureus enzyme (SaHPPK) (IC50 ∼ 41 µM), and determined the structure of the SaHPPK/8-MG complex. Here we present the synthesis of a series of guanine derivatives, together with their HPPK binding affinities, as determined by SPR and ITC analysis. The binding mode of the most potent was investigated using 2D NMR spectroscopy and X-ray crystallography. The results indicate, firstly, that the SH group of 8-MG makes a significant contribution to the free energy of binding. Secondly, direct N 9 substitution, or tautomerization arising from N 7 substitution in some cases, leads to a dramatic reduction in affinity due to loss of a critical N 9-H···Val46 hydrogen bond, combined with the limited space available around the N 9 position. The water-filled pocket under the N 7 position is significantly more tolerant of substitution, with a hydroxyl ethyl 8-MG derivative attached to N 7 (compound 21a) exhibiting an affinity for the apo enzyme comparable to the parent compound (KD ∼ 12 µM). In contrast to 8-MG, however, 21a displays competitive binding with the ATP cofactor, as judged by NMR and SPR analysis. The 1.85 Å X-ray structure of the SaHPPK/21a complex confirms that extension from the N 7 position towards the Mg2+-binding site, which affords the only tractable route out from the pterin-binding pocket. Promising strategies for the creation of more potent binders might therefore include the introduction of groups capable of interacting with the Mg2+ centres or Mg2+ -binding residues, as well as the development of bitopic inhibitors featuring 8-MG linked to a moiety targeting the ATP cofactor binding site.

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Section: Resultsmentioning

confidence: 99%

Exploring the Chemical Space around 8-Mercaptoguanine as a Route to New Inhibitors of the Folate Biosynthesis Enzyme HPPK

et al. 2013

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“…N-Bromosuccinimide has also been shown to brominate guanosine and adenosine, but not inosine, using DMF as the solvent. (388) It is perhaps conceivable that the reaction of the purine nucleoside with N-bromoacetamide proceeds via a free radical and not by an electrophilic mechanism, but the exact nature of this reaction has not been elucidated. The fact that the reaction proceeds readily without the usual radical initiators (e.g., light, peroxide) would seem to support the heterolytic mechanism.…”

Section: Bromina/ionmentioning

confidence: 99%

Synthesis and Properties of Purine Nucleosides and Nucleotides

Srivastava

Robins²,

Meyer

1988

Chemistry of Nucleosides and Nucleotides

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“…The 5-bromination of uracil derivatives has been effected with Br 2 /Ac 2 O/AcOH, 2 Br 2 /H 2 O, 10 N - bromosuccinimide (NBS) in DMF 11 or ionic liquids, 12 combination of 3-chloroperoxybenzoic acid/HBr in aprotic solvents, 13 ceric ammonium nitrate (CAN)/LiBr in protic or aprotic solvents, 14 or KBr/Oxone. 15 Bromination of cytidine at C-5 has been accomplished with Br 2 /CCl 4 /hν 16 or NBS in DMF 11 or ionic liquids. 12 The 8-bromination of adenine or guanine nucleosides has been typically achieved with Br 2 /AcOH/AcONa 17 or NBS/DMF.…”

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confidence: 99%

“…12 The 8-bromination of adenine or guanine nucleosides has been typically achieved with Br 2 /AcOH/AcONa 17 or NBS/DMF. 11 …”

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Bromination at C-5 of pyrimidine and C-8 of purine nucleosides with 1,3-dibromo-5,5-dimethylhydantoin

Rayala

Wnuk

2012

Tetrahedron Letters

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Treatment of the protected and unprotected nucleosides with 1,3-dibromo-5,5- dimethylhydantoin in aprotic solvents such as CH2Cl2, CH3CN, or DMF effected smooth bromination of uridine and cytidine derivatives at C-5 of pyrimidine rings as well as adenosine and guanosine derivatives at C-8 of purine rings. Addition of Lewis acids such as trimethylsilyl trifluoromethanesulfonate enhanced efficiency of bromination.

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Bromination of nucleosides

Cited by 19 publications

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Exploring the Chemical Space around 8-Mercaptoguanine as a Route to New Inhibitors of the Folate Biosynthesis Enzyme HPPK

Exploring the Chemical Space around 8-Mercaptoguanine as a Route to New Inhibitors of the Folate Biosynthesis Enzyme HPPK

Synthesis and Properties of Purine Nucleosides and Nucleotides

Bromination at C-5 of pyrimidine and C-8 of purine nucleosides with 1,3-dibromo-5,5-dimethylhydantoin

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