α-Azido Bisphosphonates: Synthesis and Nucleotide Analogues

Chamberlain, Brian T.; Upton, Thomas G.; Kashemirov, B. A.; McKenna, Charles E.

doi:10.1021/jo200045a

Cited by 23 publications

(25 citation statements)

References 35 publications

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“…14−16 Both criteria are satisfied by our probes, in which X and Y in the CXY moiety are H, F, Cl, or Br 16,18,19 as well as other useful substituents such as CH 3 and N 3 30 and for which a range of pol β ternary complex active-site structures have been determined. 6,14,16,18−20,30 Furthermore, we have addressed the problem of CXY stereochemistry where X ≠ Y synthetically, analytically, kinetically, and structurally. 14,16,17,31 …”

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confidence: 69%

Transition State in DNA Polymerase β Catalysis: Rate-Limiting Chemistry Altered by Base-Pair Configuration

Oertell

Chamberlain²,

Wu³

et al. 2014

Biochemistry

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102

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Kinetics studies of dNTP analogues having pyrophosphate-mimicking β,γ-pCXYp leaving groups with variable X and Y substitution reveal striking differences in the chemical transition-state energy for DNA polymerase β that depend on all aspects of base-pairing configurations, including whether the incoming dNTP is a purine or pyrimidine and if base-pairings are right (T•A and G•C) or wrong (T•G and G•T). Brønsted plots of the catalytic rate constant (log(kpol)) versus pKa4 for the leaving group exhibit linear free energy relationships (LFERs) with negative slopes ranging from −0.6 to −2.0, consistent with chemical rate-determining transition-states in which the active-site adjusts to charge-stabilization demand during chemistry depending on base-pair configuration. The Brønsted slopes as well as the intercepts differ dramatically and provide the first direct evidence that dNTP base recognition by the enzyme–primer–template complex triggers a conformational change in the catalytic region of the active-site that significantly modifies the rate-determining chemical step.

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confidence: 69%

Transition State in DNA Polymerase β Catalysis: Rate-Limiting Chemistry Altered by Base-Pair Configuration

Oertell

Chamberlain²,

Wu³

et al. 2014

Biochemistry

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102

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“…13 However, efforts to separate the α,β -CH(N 3 ) stereoisomers were unsuccessful. 13 ( R / S )- β,γ -CH(N 3 ) and ( R / S )- β,γ -CMe(N 3 ) dGTP also proved refractory to this method, 13 suggesting that both the substituent size and the distance of CXY group from the chiral ribose affects separation. It seemed apparent that preparation of the elusive individual β,γ -CXY stereoisomers, particularly the highly desirable monohalo derivatives, 4-5,14 required a new approach, ideally one achieving stereochemical separation at the bisphosphonate level.…”

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confidence: 99%

β,γ-CHF- and β,γ-CHCl-dGTP Diastereomers: Synthesis, Discrete ³¹P NMR Signatures, and Absolute Configurations of New Stereochemical Probes for DNA Polymerases

Zakharova²,

Kashemirov³

et al. 2012

J. Am. Chem. Soc.

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100

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Deoxynucleoside 5′-triphosphate analogues in which the β,γ-bridging oxygen has been replaced with a CXY group are useful chemical probes to investigate DNA polymerase catalytic and base selection mechanisms. A limitation of such probes has been that conventional synthetic methods generate a mixture of diastereomers when the bridging carbon substitution is non-equivalent (X ≠ Y). We report here a general solution to this long-standing problem with four examples of individual β,γ-CXY dNTP diastereomers: (S)- and (R)-β,γ-CHCl dGTP (12a-1, 12a-2) and (S)- and (R)-β,γ-CHF dGTP (12b-1, 12b-2). Central to their preparation was conversion of the achiral parent bisphosphonic acids to P,C-dimorpholinamide derivatives (7) of their (R)-mandelic acid monoesters (6), which provided access to the individual diastereomers 7a-1, 7a-2, 7b-1, and 7b-2 by preparative HPLC. Selective acidic hydrolysis of the P-N bond then afforded the “ portal ” diastereomers 10, which were readily coupled to morpholine-activated dGMP. Removal of the chiral auxiliary by H2 (Pd/C) afforded the four individual diastereomeric nucleotides (12), which were characterized by 31P, 1H and 19F NMR, and by MS. After treatment with Chelex®-100 to remove traces of paramagnetic ions, at pH ~10 the diastereomer pairs 12a and 12b exhibit discrete Pα and Pβ 31P resonances. The more upfield Pα and more downfield Pβ resonances (and also the more upfield 19F NMR resonance in 12b) are assigned to the (R) configuration at the Pβ-CHX-Pγ carbons, based on the absolute configurations of the individual diastereomers as determined by X-ray crystallographic structures of their ternary complexes with DNA-pol β.

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“…As far as azide‐containing BP precursors are concerned, only the synthesis of few examples of α‐azido and γ‐azido BPs have been described in the literature, but no click reactions have been reported for these compounds. Conversely, syntheses of and reactions with β‐azido BP are highly discussed topics .…”

Section: Resultsmentioning

confidence: 99%

Diketopyrrolopyrrole Bis‐Phosphonate Conjugate: A New Fluorescent Probe for In Vitro Bone Imaging

Chiminazzo

Borsato

Favero³

et al. 2019

Chemistry A European J

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The synthesis of a conjugate molecule between an unusual red‐fluorescent diketopyrrolopyrrole (DPP) unit and a bis‐phosphonate (BP) precursor by a click‐chemistry strategy to target bone tissue and monitor the interaction is reported. After thorough investigation, conjugation through a triazole unit between a γ‐azido rather than a β‐azido BP and an alkyne‐functionalized DPP fluorophore group turned out to be the winning strategy. Visualization of the DPP‐BP conjugate on osteoclasts and specific antiresorption activity were successfully demonstrated.

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α-Azido Bisphosphonates: Synthesis and Nucleotide Analogues

Cited by 23 publications

References 35 publications

Transition State in DNA Polymerase β Catalysis: Rate-Limiting Chemistry Altered by Base-Pair Configuration

Transition State in DNA Polymerase β Catalysis: Rate-Limiting Chemistry Altered by Base-Pair Configuration

β,γ-CHF- and β,γ-CHCl-dGTP Diastereomers: Synthesis, Discrete ³¹P NMR Signatures, and Absolute Configurations of New Stereochemical Probes for DNA Polymerases

Diketopyrrolopyrrole Bis‐Phosphonate Conjugate: A New Fluorescent Probe for In Vitro Bone Imaging

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α-Azido Bisphosphonates: Synthesis and Nucleotide Analogues

Cited by 23 publications

References 35 publications

Transition State in DNA Polymerase β Catalysis: Rate-Limiting Chemistry Altered by Base-Pair Configuration

Transition State in DNA Polymerase β Catalysis: Rate-Limiting Chemistry Altered by Base-Pair Configuration

β,γ-CHF- and β,γ-CHCl-dGTP Diastereomers: Synthesis, Discrete 31P NMR Signatures, and Absolute Configurations of New Stereochemical Probes for DNA Polymerases

Diketopyrrolopyrrole Bis‐Phosphonate Conjugate: A New Fluorescent Probe for In Vitro Bone Imaging

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β,γ-CHF- and β,γ-CHCl-dGTP Diastereomers: Synthesis, Discrete ³¹P NMR Signatures, and Absolute Configurations of New Stereochemical Probes for DNA Polymerases