3520
K. L. Smith et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3517–3520
5. Charles, S. A.; Harris, J. M.; Pedder, S.; Kumar, S.
Modern Drug Discovery 2000, 5, 59.
Most compounds show low cytotoxicity with an excep-
tion of 4, which nonetheless still shows a reasonably
high selectivity index (CC50/EC50).
6. (a) Hovi, T. Med. Biol. 1983, 61, 196; (b) Moyer, S. A.;
Holmes, K. S. Virology 1979, 98, 99; (c) Larsen, C. J.;
Mauchauffe, M.; Hamelin, R.; Peraudeau, L.; Fedele, L.;
Traitian, A. Nucleic Acids Res. 1979, 6, 1547; (d)
Bergstorm, D. E.; Brattesami, A. J.; Ogawa, M. K.;
Reddy, A.; Schweickert, M. J.; Balzarini, J.; De Clercq, E.
J. Med. Chem. 1984, 27, 285; (e) De Clercq, E.; Balzarini,
J.; Madej, D.; Hansske, F.; Robins, M. J. J. Med. Chem.
1987, 30, 481; (f) Schneller, S. W.; Thompson, R. D.;
Cory, J. G.; Olsson, R. A.; De Clercq, E.; Kim, I. K.;
Chiang, P. K. J. Med. Chem. 1984, 27, 924.
7. Kucera, L. S.; Iyer, N. P.; Puckett, S. H.; Buckheit, R. W.,
Jr.; Westbrook, L.; Toyer, B. R.; White, E. L.; Germany-
Decker, J. M.; Shannon, W. M.; Chem, R. C.; Nassiri, M.
R.; Shipman, C.; Townsend, L. B.; Drach, J. C. AIDS Res.
Hum. Retroviruses 1993, 9, 307.
In summary, N4 substituted b-
bines 4–6 were synthesized. We have established an
efficient coupling of a 20-b-C-methyl-b-
-ribofuranose
4-amino-7-bromo-5-cyanopyrrolo[2,3-d]pyrimi-
D-ribofuranosyl triciri-
D
with
dine.
Employing this strategy, new N4 and 6-N substituted 20-
b-C-methyl-b- -ribofuranosyl triciribines 7–13 were
D
synthesized as potential anti-HCV agents. Some of them
were found to exhibit anti-viral activity in HCV replicon
cell culture with minimal cytotoxicity. These results
should promote the synthetic studies of other 20-b-C-
methyl nucleosides, such as the biologically active toy-
ocamycin and sangivamycin, as potential therapeutics
against human diseases.
8. (a) Feun, L. G.; Blessing, J. A.; Barrett, R. J.; Hanjani, P.
Am. J. Clin. Oncol. 1993, 16, 506; (b) O’Connell, M. J.;
Rubin, J.; Hahn, R. G.; Kvols, L. K.; Moertel, C. G.
Cancer Treat. Rep. 1987, 71, 333.
9. Porcari, A. R.; Borysko, K. Z.; Ptak, R. G.; Breitenbach,
J. M.; Wotring, L. L.; Drach, J. C.; Townsend, L. B.
Nucleos. Nucleot. 1999, 11, 2475.
10. Porcari, A. R.; Ptak, R. G.; Borysko, K. Z.; Breitenbach,
J. M.; Vittori, S.; Wotring, L. L.; Drach, J. C.; Townsend,
L. B. J. Med. Chem. 2000, 43, 2438.
11. Porcari, A. R.; Ptak, R. G.; Borysko, K. Z.; Breitenbach,
J. M.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 2000,
43, 2457.
Acknowledgements
The authors thank Jeffrey Abt and Jenny Song for the
synthesis of 25.
12. Murai, Y.; Shiroto, H.; Ishizaki, T.; Iimori, T.; Kodama,
Y.; Ohtsuka, Y.; Oishi, T. Heterocycles 1992, 33, 391.
13. Migliaccio, G.; Tomassini, J. E.; Carroll, S. S.; Tomei, L.;
Altamura, S.; Bhat, B.; Bartholomew, L.; Rosserman, M.
R.; Ceccacci, A.; Colwell, L. F.; Cortese, R.; De France-
sco, R.; Eldrup, A. B.; Gethy, K. L.; Hou, X. S.;
LaFemina, R. L.; Ludmerer, S. W.; MacCoss, M.;
McMasters, D. R.; Stahlhut, M. W.; Olsen, D. B.;
Hazuda, D. J.; Flores, O. A. J. Biol. Chem. 2003, 278,
49164.
References and notes
1. (a) Choo, Q. L.; Kuo, G.; Weiner, A. J.; Overby, L. R.;
Bradley, D. W.; Houghton, M. Science 1989, 244, 359; (b)
Kuo, G.; Choo, Q. L.; Alter, H. J.; Gitnick, G. L.;
Redeker, A. G.; Purcell, R. H.; Miyamura, T.; Dienstag, J.
L.; Alter, M. J.; Stevens, C. E. Science 1989, 244, 362; (c)
Choo, Q. L.; Richman, K. H.; Han, J. H.; Berger, K.; Lee,
C.; Dong, C.; Gallegos, C.; Coit, D.; Medina-Selby, A.;
Barr, P. J.; Weiner, A. J.; Bradley, D. W.; Kuo, G.;
Houghton, M. Proc. Natl. Acad. Sci. U.S.A. 1991, 88,
2451.
2. (a) World Health Organization. J. Viral. Hepatitis 1999, 6,
35; (b) National Institutes of Health Consensus Develop-
ment Conference Statement: Management of Hepatitis C,
2002.
3. Davis, G. L.; Balart, L. A.; Schiff, E. R.; Kindsay, K.;
Bodenheimer, H. C., Jr.; Perrillo, R. P.; Carey, W.;
Jacobson, I. M.; Payne, J.; Dienstag, J. L. N. Eng. J. Med.
1989, 321, 1501.
4. (a) McHutchison, J. Am. J. Med. 1999, 107, 56S; (b)
McHutchison, J. G.; Gordon, S. C.; Schiff, E. R.;
Shiffman, M. L.; Lee, W. M.; Rustgi, V. K.; Goodman,
Z. D.; Ling, M. H.; Cort, S.; Albrecht, J. K. N. Engl. J.
Med. 1998, 339, 1485; (c) Poynard, T.; Marcellin, P.; Lee,
S. S.; Niederau, C.; Minuk, G. S.; Ideo, G.; Vain, V.;
Heathcote, J.; Zeuzem, S.; Trepo, C.; Albrecht, J. K.
Lancet 1998, 352, 1426.
€
14. (a) Lohmann, V.; Korner, F.; Koch, J. O.; Herian, U.;
Theilmann, L.; Bartenschlager, R. Science 1999, 285, 110;
(b) Bartenschlager, R.; Lohmann, V. J. Gen. Virol. 2000,
81, 1631; (c) Bartenschlager, R.; Lohmann, V. Antiviral
Res. 2001, 52, 1; (d) Bartenschlager, R. Nat. Rev.––Drug
Discovery 2002, 1, 911.
15. Hinshaw, B. C.; Leonoudakis, O.; Schram, K. H.;
Towsend, L. B. J. Chem. Soc., Perkin Trans. 1: Org.
Bioorg. Chem. 1975, 1248.
16. Gunic, E.; Girardet, J.-L.; Pietrzkowski, Z.; Esler, C.;
Wang, G. Bioorg. Med. Chem. 2001, 9, 163.
17. (a) Wolfe, M. S.; Harry-O’kuru, R. E. Tetrahedron Lett.
1995, 36, 7611; (b) Franchetti, P. F.; Cappellacci, S. M.;
Trincavelli, L.; Martini, C.; Mazzoni, M. R.; Lucacchini,
A.; Grifantini, M. J. Med. Chem. 1998, 41, 1708.
18. All compounds in this study were characterized by 1H
NMR and MS spectroscopic analyses, and the purity was
assessed by HPLC.
19. Barltrop, J. A.; Owen, T. C.; Cory, A. H.; Cory, J. G.
Bioorg. Med. Chem. Lett. 1991, 1, 611.