Isonucleosides incorporating universal bases

Article abstract of DOI:10.1081/NCN-100002362

Enantiomeric isodideoxynucleosides of the (S,S) and (R,R) families with the universal base, imidazole-4-carboxamide as the nucleobase, were synthesized as biological mimics of anti-HIV active D- and L-related isodideo-xyadenosines. In vitro anti-HIV evaluation in CEM cells of these target compounds showed that they were inactive. Further antiviral studies are in progress.

Full text of DOI:10.1081/NCN-100002362

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ISONUCLEOSIDES INCORPORATING UNIVERSAL BASES
Vasu Nair a , David S. Sosnouski a & Qingming Zhu a
a Department of Chemistry , The University of Iowa , Iowa City, Iowa, 52242, U.S.A.
Published online: 07 Feb 2007.
To cite this article: Vasu Nair , David S. Sosnouski & Qingming Zhu (2001) ISONUCLEOSIDES INCORPORATING UNIVERSAL
BASES, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 735-738, DOI: 10.1081/NCN-100002362
To link to this article: http://dx.doi.org/10.1081/NCN-100002362
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 735–738 (2001)
ISONUCLEOSIDES INCORPORATING
UNIVERSAL BASES
Vasu Nair,∗ David S. Sosnouski, and Qingming Zhu
Department of Chemistry, The University of Iowa,
Iowa City, Iowa 52242
ABSTRACT
Enantiomeric isodideoxynucleosides of the (S,S) and (R,R) families with the
universal base, imidazole-4-carboxamide as the nucleobase, were synthesized
asbiologicalmimicsofanti-HIVactiveD-andL-relatedisodideo-xyadenosines.
In vitro anti-HIV evaluation in CEM cells of these target compounds showed
that they were inactive. Further antiviral studies are in progress.
The concept of a universal base that can base-pair all four natural bases
found in nucleosides has been the subject of a number of recent studies (1–4).
Irregular base-pairing occurs in nature and has been of importance in the under-
standing of the interpretation of the genetic code by tRNA molecules. Abnormal
base-pairing also occurs in DNA. It was reported by Ohtsuka et al. (4) that 2ꢀ-
deoxyinosine (dI) could behave as a universal nucleoside and participate in base-
pairing with all four natural deoxynucleosides. Its binding to cytosine and thymine
occurs via normal Watson-Crick base-pairing, but its binding to adenine occurs
via Hoogsteen base-pairing. However, dI shows a distinct preference for base-
pairing with deoxycytidine (dC). The compound, 1-(2-deoxy-β-D-ribofuranosyl)
imidazole-4-carboxamide (dICAR – shown below, Fig. 1), has been reported by
Sala et al. (2) and Johnson et al. (1) to behave also as a universal nucleoside but
exhibiting a preference for behaving as a dA mimic.
For a number of years, we have investigated the chemistry and biology of
isomeric nucleosides or isonucleosides (5–7). Of the many isodideoxynucleosides
∗ Corresponding author.
735
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
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NAIR, SOSNOUSKI, AND ZHU
Figure 1.
synthesized in our research group, the most anti-HIV active member is (S,S)-
isodideoxyadenosine which, as its triphosphate, inhibits HIV reverse transcriptase
at the low nM level (6,7). It appears that potent anti-HIV activity of these isonu-
cleosides is confined to compounds with the nucleobase, adenine. Substitution
of other natural nucleic acid bases in place of adenine results in loss of antivi-
ral activity (7,8). The question of whether the universal nucleobase, imidazole-
4-carboxamide, capable of mimicing adenine could be substituted for adenine
in these isonucleosides has not been investigated. This paper reports our
results on the synthesis (Scheme 1) and anti-HIV activity studies of isonucleosides
Scheme 1.

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ISONUCLEOSIDES INCORPORATING UNIVERSAL BASES
737
of both the D- and L-related families that contain the base, imidazole-4-
carboxamide.
The key carbohydrate intermediate for the synthesis of the L-related target
compound, 6, was tosylate 3, which was prepared from 1 in several known steps in-
cluding two deoxygenations (Scheme 1) (9). Coupling of 3 with methylimidazole-
4-carboxylate in the presence of K2CO3 and 18-crown-6 gave 4 (32%) and its
3-substituted isomer 5 (24%) which were separated chromatographically and iden-
1
tified by H and 13C NMR data. Interestingly, the Mitsunobu coupling reaction
of the alcohol precursor of 3 with methylimidazole-4-carboxylate gave only low
yields of the coupling products. Compound 4 was converted to the target mole-
cule 6 (S,S-isomer) in 80% yield by treatment with NH4Cl/NH4OH (10). The
enantiomeric target molecule 11 was synthesized by a related route with com-
pound 8 as the key intermediate. Intermediate 8 was prepared from the rear-
rangement of 7 with MeOH/HCl (11). A summary of the main steps involved
in the synthesis of 11 is shown in Scheme 1. These two D- and L-related target
compounds were screened for antiviral activity against HIV-1 in CEM-SS cells
and were found to be inactive. Further evaluations against other viruses are in
progress.
ACKNOWLEDGMENTS
We thank the NIH (NIAID) for support of our research work and the NCI for
the antiviral evaluations.
REFERENCES
1. Johnson, W. T.; Zhang, P.; Bergstrom, D. E. Nucleic Acids Res. 1997, 25, 559–
567.
2. Sala, M.; Pezo, V.; Pochet, S.; Wain-Hobson, S. Nucleic Acids Res. 1996, 24,
3302–3306.
3. Bergstrom, D. E.; Zhang, P.; Johnson, W. T. Nucleosides & Nucleotides 1996, 15,
59–68.
4. Ohtsuka, E.; Matsuki, S.; Ikehara, M.; Takahashi, Y.; Matsubara, K. J. Biol. Chem.
1985, 260, 2605–2608.
5. Nair, V.; Nuesca, Z. M. J. Am. Chem. Soc. 1992, 114, 7951–7953.
6. Nair, V.; St. Clair, M.; Reardon, J. E.; Krasny, H. C.; Hazen, R. J.; Paff, M. T.;
Boone, L. R.;Tisdale, M.;Najera, I.;Dornsife, R. E.;Everett, D. R.;Borroto-Esoda, K.;
Yale, J. L.; Zimmerman, T. P.; Rideout, J. L. Antimicrob. Agents Chemother. 1995,
39, 1993–1999.
7. Nair, V.; Jahnke, T. S. Antimicrob. Agents Chemother, 1995, 39, 1017–1029.
8. Zintek, L. B.; Jahnke, T. S.; Nair, V. Nucleosides & Nucleotides 1996, 15, 69–84.
9. Bolon, P. J.; Sells, T. B.; Nuesca, Z. M.; Purdy, D. F.; Nair, V. Tetrahedron 1994, 50,
7747–7764.
10. Data for compound 6: 1H NMR (CD3OD): δ 1.92 (1H, m), 2.55 (1H, m), 3.58 (1H,
m), 3.74 (1H, m), 3.95 (3H, m), 4.91 (1H, m), 7.78 (2H); 13C NMR (CD3OD):

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NAIR, SOSNOUSKI, AND ZHU
δ 36.6, 59.4, 63.9, 74.6, 81.4, 122.0, 137.3, 138.2, 167.3; λmax 235 nm, FAB HRMS:
1
calc. for (M + H)+ 212.1011, found 212.1031. H NMR data clearly differentiated
between product 6 and its regioisomer as the chemical shift of the hydrogen on the
carbon bearing the base was at δ 4.91 for 6 and at δ 5.69 for its regioisomer. Fur-
ther confirmation of structure and stereochemistry for 6 and 11 came from NOESY
experiments.
11. Defaye, J.; Horton, D.; Muesser, M. Carbohydr. Res. 1971, 20, 305–318.

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