Deoxyribonolactone lesion in DNA: Synthesis of fluorinated analogues

Article abstract of DOI:10.1081/NCN-120022744

Mono- and difluorinated derivatives of 2-deoxyribonolactone were synthesized using diastereoselective Reformatski reaction as a key step.

Full text of DOI:10.1081/NCN-120022744

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Deoxyribonolactone Lesion in DNA: Synthesis of
Fluorinated Analogues
Caroline Crey a , Pascal Dumy a , Jean Lhomme a & Mitsuharu Kotera a b
a LEDSS - UMR5616 associé au CNRS, BP53 , Université Joseph Fourier , Grenoble, France
b LEDSS - UMR5616 associé au CNRS, BP53 , Université Joseph Fourier , F-38041, Grenoble,
France
Published online: 31 Aug 2006.
To cite this article: Caroline Crey , Pascal Dumy , Jean Lhomme & Mitsuharu Kotera (2003) Deoxyribonolactone Lesion in
DNA: Synthesis of Fluorinated Analogues, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 1093-1095, DOI: 10.1081/
NCN-120022744
To link to this article: http://dx.doi.org/10.1081/NCN-120022744
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1093–1095, 2003
Deoxyribonolactone Lesion in DNA: Synthesis of
Fluorinated Analogues
Caroline Crey, Pascal Dumy, Jean Lhomme, and
*
Mitsuharu Kotera
´
´
LEDSS - UMR5616 associe au CNRS, BP53, Universite Joseph Fourier,
Grenoble, France
ABSTRACT
Mono- and difluorinated derivatives of 2-deoxyribonolactone were synthesized
using diastereoselective Reformatski reaction as a key step.
Key Words: Fluorinated derivatives; Deoxyribonolactone; DNA damage;
Synthesis.
Deoxyribonolactone in DNA is an oxidized abasic site damage that is produced
by a variety of physical and chemical agents such as g-irradiation and ene-diyne anti-
biotics. The extent and biological significance of the lesion are poorly documented
due to the high lability of the damaged DNA. Recently we described the chemistry
of deoxyribonolactone lesion in DNA that was investigated using oligonucleotides
prepared, as already reported, from oligonucleotide precursors containing a photo-
active nitroindole residue.[1–3] The cleavage kinetics were investigated using capillary
´
*Correspondence: Mitsuharu Kotera, LEDSS - UMR5616 associe au CNRS, BP53, Univer-
´
uif-grenoble.fr.
site Joseph Fourier, F-38041 Grenoble, France; Fax: þ33 4 7651 4946; E-mail: mitsu.kotera@
1093
DOI: 10.1081/NCN-120022744
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1094
Crey et al.
Scheme 1.
electrophoresis and it was found that the rate of cleavage of the lesion is extremely
sensitive to pH, temperature. Here we describe the synthesis of fluorinated deriva-
tives of deoxyribonolactone.
The fluorinated derivatives of deoxyribonolactone represent a new type of lesion
model. When these residues are incorporated in DNA, they may be useful as stable
analogs of the deoxyribonolactone lesion for future structural and biological studies.
The synthetic route is outlined in the following schemes. Difluorodeoxyribonolac-
tone 1 was synthesized in two steps as described previously using diastereoselective
Reformatsky reaction as the first step.[4] It has been shown that the free difluorolac-
tone 1 exists mainly as an open chain structure in aqueous solution. The two isomeric
monofluorodeoxyribonolactones 2 and 3 were synthesized using the similar synthetic
Scheme 1. The stereochemistry of two isomers was determined by 2D NOESY
spectra. 2: Rf ¼ 0.43 (AcOEt:cyclohexane ¼ 1:2), 1H NMR (300 MHz, CDCl3): d
ppm ¼ 7.92 (m, 2H); 7.82 (m, 2H); 7.25 (m, 4H); 5.74 (m, H-3); 5.48 (dd, H-2,
J ¼ 48 and 6 Hz); 4.97 (m, H-4); 4.66 (m, 2H, H-5); 2.41 (s, 6H). 19F NMR
(283 MHz, CDCl3): d ppm ¼ ꢀ214.3 (d, J ¼ 48 Hz). MS: (DCI, NH3 þ isobutane)
m=z 387 [M þ H]þ Anal.Calcd. for C21H19FO6: C, 65.28; H, 4.96; Found: C,
64.67; H, 4.88. 3: Rf ¼ 0.37 (AcOEt:cyclohexane ¼ 1:2), 1H NMR (300 MHz,
CDCl3): d ppm ¼ 7.89 (m, 4H); 7.23 (m, 4H); 5.82 (m, H-3); 5.45 (dd, H-2, J ¼ 49
and 5 Hz); 4.79 (m, H-4); 4.71 (m, 2H, H-5); 2.42 (s, 3H); 2.38 (s, 6H). 19F NMR
(283 MHz, CDCl3): d ppm ¼ ꢀ199.5 (dd, J ¼ 49 and 19 Hz). MS: (DCI, NH3 þ
isobutane) m=z 387 [M þ H]þ Anal.Calcd. for C21H19FO6: C, 65.28; H, 4.96; Found:
C, 65.03; H, 4.86.

Deoxyribonolactone Lesion in DNA
1095
REFERENCES
1. Roupioz, Y.; Lhomme, J.; Kotera, M. Chemistry of the 2-deoxyribonolactone
lesion in oligonucleotides: cleavage kinetics and products analysis. J. Am. Chem.
Soc. 2002, 124, 9129–9135.
2. Kotera, M.; Roupioz, Y.; Defrancq, E.; Bourdat, A.-G.; Garcia, J.;
Coulombeau, C.; Lhomme, J. The 7-nitroindole nucleoside as a photochemical
precursor of 20-deoxyribonolactone: access to DNA fragments containing this
oxidative abasic lesion. Chem.-Eur. J. 2000, 6, 4163–4169.
3. Kotera, M.; Bourdat, A.-G.; Defrancq, E.; Lhomme, J. A highly efficient synth-
esis of oligodeoxyribonucleotides containing the 20-deoxyribonolactone lesion.
J. Am. Chem. Soc. 1998, 120, 11,810–11,811.
4. Chou, T.S.; Heath, P.C.; Patterson, L.E.; Poteet, L.M.; Lakin, R.E.; Hunt, A.H.
Stereospecific synthesis of 2-deoxy-2,2-difluororibonolactone and its use in the
preparation of 20-deoxy-20,20-difluoro-b-D-ribofuranosyl pyrimidine nucleo-
sides: the key role of selective crystallization. Synthesis 1992, 6, 565–570.