R. K. Ujjinamatada et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2285–2288
2287
being present.27,28 By contrast, and to our surprise, no
such tight complex formation was observed with either
a DNA or an RNA substrate when the same experi-
ments were conducted using the nucleoside analogue 4.
This observation is indeed exciting as it implies that
the compound must be interacting directly with the en-
zyme. The observed difference in activity resulting from
the different types of substrates employed may well be
due either to the differential conformational effects
exerted by the enzyme–substrate complex upon subse-
quent binding of the inhibitor to the protein or due to
those caused by the enzyme–inhibitor complex upon
eventual binding of a DNA or an RNA substrate. These
speculations, however, are only tentative at this point.
20. Abe, M.; Shiosaki, K.; Hammar, L.; Sonoda, K.; Xing, L.;
Kuzuhara, S.; Kino, Y.; Cheng, R. H. Virus Res. 2006,
121, 152.
21. Ramesh, K.; Panzica, R. P. J. Chem. Soc., Perkin Trans. 1
1989, 1769.
22. Murakami, T.; Otsuka, M.; Ohno, M. Tetrahedron Lett.
1982, 23, 4729.
23. Kazimierczuk, Z.; Cottam, H. B.; Revankar, G. R.;
Robins, R. K. J. Am. Chem. Soc. 1984, 106, 6379.
24. Tocik, Z.; Earl, R. A.; Beranek, J. Nucleic Acids Res. 1980,
8, 4755.
25. Marquez, V. E.; Liu, P. S.; Linevsky, J. K. J. Org. Chem.
1982, 47, 1712.
26. Experimental. Preparation and physicochemical proper-
ties of the compounds are as follows: Ethyl 5-diethoxym-
ethyl-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl) imidazole-
4-carboxylate (2).
Step 1: Preparation of sodium salt of ethyl 5-diethoxym-
ethyl-imidazole-4-carboxylate: To a solution of ethyl 5-
diethoxymethylimidazole-4-carboxylate (0.267 g, 1 mmol)
in dry acetonitrile (10 mL), sodium hydride (80 mg,
2 mmol) was added and the mixture was stirred at room
temperature under nitrogen atmosphere for 30 min.
Step 2: Reaction of sodium salt of ethyl 5-diethoxymethyl-
imidazole-4-carboxylate with 1-O-acetyl-2,3,5-O-benzoyl-
b-D-ribofuranosyl iodide: To a solution of 1-O-acetyl-
2,3,5-tri-O-benzoyl-b-D-ribofuranose (0.567 g, 1 mmol) in
dry benzene (5 mL), iodotrimethylsilane (0.225 mL,
1.6 mmol) was added dropwise. The mixture was swirled
for 10 min at room temperature and then it was added
dropwise to a stirred suspension of the above sodium salt
of ethyl 5-diethoxymethylimidazole-4-carboxylate. The
temperature of the reaction mixture was gradually raised
to 50 ꢁC and was stirred for 2 h. The reaction mixture was
then brought to room temperature, acetonitrile was
removed under vacuum, and the residue was purified by
column chromatography using hexanes/ethyl acetate (3:1)
as an eluting solvent. Appropriate fractions were pooled
and evaporated under vacuum. Gummy residue was
crystallized from benzene-pet ether to obtain colorless,
flaky solid. Yield 0.595 g, 87%; mp 43–45 ꢁC, Rf = 0.21
(hexanes/ethyl acetate 3:1); IR, 1718, 1703, 1577,
Acknowledgments
The research was supported in part by Grants (# 5 RO1
AI55452 and #1 R21 AI071802) from the National
Institute of Allergy and Infectious Diseases (NIAID)
of the National Institutes of Health, Bethesda,
Maryland, and by an unrestricted grant from Nabi
Biopharmaceuticals, Rockville, Maryland.
References and notes
1. Ujjinamatada, R. K.; Agasimundin, Y. S.; Zhang, P.;
Hosmane, R. S. Nucleosides Nucleotides Nucleic Acids
2005, 24, 1775.
2. Ujjinamatada, R. K.; Hosmane, R. S. Tetrahedron Lett.
2005, 46, 6005.
3. Diamond, M. S.; Klein, R. S. Trends Microbiol. 2006, 14,
287.
4. Davis, L. E.; DeBiasi, R.; Goade, D. E.; Haaland, K. Y.;
Harrington, J. A.; Harnar, J. B.; Pergam, S. A.; King, M.
K.; DeMasters, B. K.; Tyler, K. L. Ann. Neurol. 2006, 60,
286.
5. Hayes, E. B.; Gubler, D. J. Annu. Rev. Med. 2006, 57, 181.
6. Dufour, D. R. Molecular Diagnostics (2nd ed.) 2006, 461.
7. Toniutto, P.; Fabris, C.; Pirisi, M. Expert Opin. Pharmac-
other. 2006, 7, 2025.
8. MacDonald, A.; Harris, M. Liver Dis. 2006, 2, 439.
9. Neyts, J. Antiviral Res. 2006, 71, 363.
10. Huang, Z.; Murray, M. G.; Secrist, J. A. Antiviral Res.
2006, 71, 351.
11. Pol, S.; Mallet, V. O. Expert Opin. Biol. Ther. 2006, 6, 923.
12. Fink, J.; Gu, F.; Vasudevan, S. G. Rev. Med. Virol. 2006,
16, 263.
13. Lin, C.-F.; Wan, S.-W.; Cheng, H.-J.; Lei, H.-Y.; Lin, Y.-
S. Viral Immunol. 2006, 19, 127.
1501 cmꢀ1 1H NMR (300 MHz, CDCl3) d 8.1 (m, 7H,
;
Ar–H and imidazole CH), 7.59–7.29 (m, 9H, Ar–H), 6.82
(d, J = 3.9 Hz, 1H, 10-H), 6.37 (s, 1H, CH), 5.60 (m, 2H,
20-H, and 30-H), 4.8–4.4 (m, 3H, 40-, 50-, and 500-H), 4.40
(q, J = 1.8 Hz, 2H), 3.85–3.45 (m, 4H, 2CH2, 1.39 (t,
J = 6.9 Hz, 3H, CH3), 1.19 (t, J = 7.2 Hz, 3H, CH3), 1.02
(t, J = 6.9 Hz, 3H, CH3); HRMS (FAB) Calcd for
C37H38N2O11, 687.2554 (MH+); observed m/z 687.2562
(MH+).
Ethyl 5-formyl-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)
imidazole-4-carboxylate (3). A solution of ethyl 5-dieth-
oxymethyl-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)imid-
azole-4-carboxylate (0.515 g 0.75 mmol) in 80% aqueous
acetic acid (5 mL) was stirred at room temperature for
15 h. The solution was then poured into ice-water (25 mL)
and the precipitated solid was extracted with chloroform
(3 · 50 mL). The chloroform layer was washed with water
(2 · 25 mL) and dried over anhyd sodium sulfate. The
solvent was removed under vacuum and the residue was
purified by flash chromatography on silica gel, using
hexanes/ethyl acetate (2:1) as an eluting solvent. Appro-
priate fractions were pooled and evaporated under vacu-
um. The residue was triturated with methanol to obtain a
white solid. Yield 0.360 g, 78%; mp 167–169 ꢁC, Rf = 0.34
(hexanes/ethyl acetate 2:1); IR 1729, 1706, 1532,
14. Green, S.; Rothman, A. Curr. Opin. Infect. Dis. 2006, 19,
429.
15. Chaturvedi, U.; Nagar, R.; Shrivastava, R. FEMS Immu-
nol. Med. Microbiol. 2006, 47, 155.
16. Seneviratne, S. L.; Malavige, G. N.; de Silva, H. J. Trans.
R. Soc. Trop. Med. Hyg. 2006, 100, 608.
17. Parida, M.; Dash, P. K.; Tripathi, N. K.; Ambuj; Saxena,
P.; Agarwal, S.; Sahni, A. K.; Singh, S. P.; Rathi, A. K.;
Bhargava, R.; Abhyankar, A.; Verma, S. K.; Lakshmana
Rao, P. V.; Sekhar, K. Emerging Infect. Dis. 2006, 12,
1427.
18. Chen, S. O.; Chang, T. J.; Stone, G.; Chen, C. H.; Liu, J. J.
Intervirology 2006, 49, 346.
19. Arya, S. C.; Agarwal, N. Vaccine 2006, 24, 5108.
;
1480 cmꢀ1 1H NMR (300 MHz, CDCl3) d 10.5 (s, 1H,
CHO), 8.17 (s, 1H, imidazole CH), 8.08–7.90 (m, 6H,