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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.

Wu Y, Zakharova VM, Kashemirov BA, Goodman MF, Batra VK, Wilson SH, McKenna CE
J Am Chem Soc 134 8734-7 (2012)
Related entries: 4do9, 4dob, 4doc

Cited: 19 times
EuropePMC logo PMID: 22397499

Abstract

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 nonequivalent (X ≠ Y). We report here a general solution to this long-standing problem with four examples of 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 prochiral parent bisphosphonic acids to the P,C-dimorpholinamide derivatives 7 of their (R)-mandelic acid monoesters, 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 "portal" diastereomers, which were readily coupled to morpholine-activated dGMP. Removal of the chiral auxiliary by H(2) (Pd/C) gave the four individual diastereomeric nucleotides 12, which were characterized by (31)P, (1)H, and (19)F NMR spectroscopy and by mass spectrometry. After treatment with Chelex-100 to remove traces of paramagnetic ions, at pH ~10 the diastereomer pairs 12a,b exhibit discrete P(α) and P(β)(31)P resonances. The more upfield P(α) and more downfield P(β) resonances (and also the more upfield (19)F NMR resonance in 12b) are assigned to the R configuration at the P(β)-CHX-P(γ) carbons on the basis of the absolute configurations of the individual diastereomers as determined from the X-ray crystallographic structures of their ternary complexes with DNA and polymerase β.

Articles - 4doa mentioned but not cited (2)

  1. β,γ-CHF- and β,γ-CHCl-dGTP diastereomers: synthesis, discrete 31P NMR signatures, and absolute configurations of new stereochemical probes for DNA polymerases. Wu Y, Zakharova VM, Kashemirov BA, Goodman MF, Batra VK, Wilson SH, McKenna CE. J Am Chem Soc 134 8734-8737 (2012)
  2. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)


Reviews citing this publication (5)

  1. Nucleoside triphosphates--building blocks for the modification of nucleic acids. Hollenstein M. Molecules 17 13569-13591 (2012)
  2. Phosphate analogues in the dissection of mechanism. Korhonen HJ, Conway LP, Hodgson DR. Curr Opin Chem Biol 21 63-72 (2014)
  3. Medicinal chemistry of fluorinated cyclic and acyclic nucleoside phosphonates. Baszczyňski O, Janeba Z. Med Res Rev 33 1304-1344 (2013)
  4. Reflections on biocatalysis involving phosphorus. Blackburn GM, Bowler MW, Jin Y, Waltho JP. Biochemistry (Mosc) 77 1083-1096 (2012)
  5. New Synthetic Methods for Phosphate Labeling. Dutta AK, Captain I, Jessen HJ. Top Curr Chem (Cham) 375 51 (2017)

Articles citing this publication (12)

  1. Transition state in DNA polymerase β catalysis: rate-limiting chemistry altered by base-pair configuration. Oertell K, Chamberlain BT, Wu Y, Ferri E, Kashemirov BA, Beard WA, Wilson SH, McKenna CE, Goodman MF. Biochemistry 53 1842-1848 (2014)
  2. Effect of β,γ-CHF- and β,γ-CHCl-dGTP halogen atom stereochemistry on the transition state of DNA polymerase β. Oertell K, Wu Y, Zakharova VM, Kashemirov BA, Shock DD, Beard WA, Wilson SH, McKenna CE, Goodman MF. Biochemistry 51 8491-8501 (2012)
  3. Probing DNA Base-Dependent Leaving Group Kinetic Effects on the DNA Polymerase Transition State. Oertell K, Kashemirov BA, Negahbani A, Minard C, Haratipour P, Alnajjar KS, Sweasy JB, Batra VK, Beard WA, Wilson SH, McKenna CE, Goodman MF. Biochemistry 57 3925-3933 (2018)
  4. Remarkably Stereospecific Utilization of ATP α,β-Halomethylene Analogues by Protein Kinases. Ni F, Kung A, Duan Y, Shah V, Amador CD, Guo M, Fan X, Chen L, Chen Y, McKenna CE, Zhang C. J Am Chem Soc 139 7701-7704 (2017)
  5. 5'-β,γ-CHF-ATP diastereomers: synthesis and fluorine-mediated selective binding by c-Src protein kinase. Hwang CS, Kung A, Kashemirov BA, Zhang C, McKenna CE. Org Lett 17 1624-1627 (2015)
  6. Two Scaffolds from Two Flips: (α,β)/(β,γ) CH2/NH "Met-Im" Analogues of dTTP. Kadina AP, Kashemirov BA, Oertell K, Batra VK, Wilson SH, Goodman MF, McKenna CE. Org Lett 17 2586-2589 (2015)
  7. DNA Polymerase β Cancer-Associated Variant I260M Exhibits Nonspecific Selectivity toward the β-γ Bridging Group of the Incoming dNTP. Alnajjar KS, Negahbani A, Nakhjiri M, Krylov IS, Kashemirov BA, McKenna CE, Goodman MF, Sweasy JB. Biochemistry 56 5449-5456 (2017)
  8. Functional interplay between NTP leaving group and base pair recognition during RNA polymerase II nucleotide incorporation revealed by methylene substitution. Hwang CS, Xu L, Wang W, Ulrich S, Zhang L, Chong J, Shin JH, Huang X, Kool ET, McKenna CE, Wang D. Nucleic Acids Res 44 3820-3828 (2016)
  9. On the observation of discrete fluorine NMR spectra for uridine 5'-β,γ-fluoromethylenetriphosphate diastereomers at basic pH. Hwang CS, Kashemirov BA, McKenna CE. J Org Chem 79 5315-5319 (2014)
  10. Kinetic Effects of β,γ-Modified Deoxynucleoside 5'-Triphosphate Analogues on RNA-Catalyzed Polymerization of DNA. Setterholm NA, Haratipour P, Kashemirov BA, McKenna CE, Joyce GF. Biochemistry 60 1-5 (2021)
  11. New Chirally Modified Bisphosphonates for Synthesis of Individual Beta,Gamma-CHX-Deoxynucleotide Diastereomers. Haratipour P, Minard C, Nakhjiri M, Negahbani A, Kashemirov BA, McKenna CE. Phosphorus Sulfur Silicon Relat Elem 194 329-330 (2019)
  12. Synthesis of 8-oxo-dGTP and its β,γ-CH2-, β, γ-CHF-, and β, γ-CF2- analogues. Zheng Y, Haratipour P, Kashemirov BA, McKenna CE. Tetrahedron Lett 67 152890 (2021)


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