Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
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Synthesis and Antiviral Activity of 2'(β)-Hydroxymethylated Carbodine Analogues Against Hepatitis C Virus

  • Hong, Joon-Hee (BK-21 Project Team, College of Pharmacy, Chosun University) ;
  • Oh, Chang-Hyun (Biomaterials Research Center, Korea Institute of Science and Technology)
  • Published : 2009.11.20
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Abstract

2'($\beta$)-Hydroxymethylated adenosine is a potent and selective inhibitor of hepatitis C virus (HCV) replication. It targets the RNA-dependent RNA polymerase of HCV, NS5B. Synthesis and antiviral evaluation of carbocyclic versions are described. The cyclopentene intermediate ($9\beta$) was successfully synthesized through sequential Johnson-Claisen orthoester rearrangement and ring-closing metathesis (RCM). Coupling of bases via a Pd(0) catalyst, selective dihydroxylation, and desilylation yielded the target nucleoside analogues. The compounds 17 and 18 were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line and showed moderate antiviral activity with toxicity up to 20.0 and 24.7 ${\mu}g/mL$, respectively.

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References

  1. Gordon, C. P.; Keller, P. A. J. Med. Chem. 2005, 48, 1 https://doi.org/10.1021/jm0400101
  2. De Francesco, R.; Migliaccio, G. Nature 2005, 436, 953 https://doi.org/10.1038/nature04080
  3. De Clercq, E. Nat. Rev. Drug Discov. 2007, 6, 1001 https://doi.org/10.1038/nrd2424
  4. Bera, S.; Malik, L.; Bhat, B.; Carroll, S. S.; MacCoss, M.; Olsen, D. B.; Tomassini, J. E.; Eldrup, A. B. Bioorg. Med. Chem. Lett. 2003, 13, 4455 https://doi.org/10.1016/j.bmcl.2003.09.008
  5. Eldrup, A. B.; Prhavc, M.; Brooks, J.; Bhat, B.; Prakash, T. P.; Song, Q.; Bera, S.; Bhat, N.; Dande, P.; Cook, P. D.; Bennett, C. F.; Carroll, S. S.; Ball, R. G.; Bosserman, M.; Burlein, C.; Colwell, L. F.; Fay, J. F.; Flores, O. A.; Getty, K.; LaFemina, R. L.; Leone, J.; MacCoss, M.; McMasters, D. R.; Tomassini, J. E.; Von Langen, D.; Wolanski, B.; Olsen, D. B. J. Med. Chem. 2004, 47, 5284 https://doi.org/10.1021/jm040068f
  6. Clark, J. L.; Hollecker, L.; Mason, J. C.; Stuyver, L. J.; Tharnish, P. M.; Lostia, S.; McBrayer, T. R.; Schinazi, R. F.; Watanabe, K. A.; Otto, M. J.; Furman, P. A.; Stec, W. J.; Patterson, S. E.; Pankiewicz, K. W. J. Med. Chem. 2005, 48, 5504 https://doi.org/10.1021/jm0502788
  7. Arimilli, M. N.; Dougherty, J. P.; Cundy, K. C.; Bischofberger, N. In Advances in Antiviral Drug Design; De Clercq, E., Ed.; Jai Press Inc.: Stamford Connecticut, 1999; vol. 3, pp 69-91
  8. El Kouni, M. H. Curr. Pharm. Design 2002, 8, 581 https://doi.org/10.2174/1381612024607171
  9. Eldrup, A. B.; Allerson, C. R.; Bennett, C. F.; Bera, S.; Bhat, B.; Bhat, N.; Bosserman, M. R.; Brooks, J.; Burlein, C.; Carrol, S. S.; Cook, P. D.; Getty, K. L.; MacCross, M.; McMasters, D. R.; Olsen, D. B.; Prakash, T. P.; Prhavc, M.; Song, Q. L.; Tomassini, J. E.; Xia, J. J. Med. Chem. 2004, 47, 2283 https://doi.org/10.1021/jm030424e
  10. Carrol, S. S.; Tomassini, J. E.; Bosserman, M.; Getty, K.; Stahlhut, M. W.; Eldrup, A. B.; Bhat, B.; Hall, D.; Simcoe, A. L.; LaFemina, R.; Rutkowski, C. A.; Wolanski, B.; Yang, Z.; Migliaccio, G.; De Francesco, R.; Kuo, L. C.; MacCross, M.; Olsen, D. B. J. Biol. Chem. 2003, 278, 11979 https://doi.org/10.1074/jbc.M210914200
  11. Yoo, B. N.; Kim, H. O.; Moon, H. R.; Seol, S. K.; Jang, S. K.; Lee, K. M.; Jeong, L. S. Bioorg. Med. Chem. Lett. 2006, 16, 4190 https://doi.org/10.1016/j.bmcl.2006.05.089
  12. Kim, J. W.; Hong, J. H. Arch. Pharm. Chem. Life Sci. 2005, 338, 399 https://doi.org/10.1002/ardp.200500118
  13. Nakata, M.; Enari, H.; Kinoshita, M. Bull. Chem. Soc. Jpn. 1982, 55, 3283 https://doi.org/10.1246/bcsj.55.3283
  14. Furstner, A. Angew. Chem. 2000, 39, 3012 https://doi.org/10.1002/1521-3773(20000901)39:17<3012::AID-ANIE3012>3.0.CO;2-G
  15. Prunet, J. Angew. Chem. 2003, 42, 2826 https://doi.org/10.1002/anie.200301628
  16. Rivkin, A.; Cho, Y. S.; Gabarda, A. E.; Yoshimura, F.; Danishefsky, S. J. J. Nat. Prod. 2004, 67, 139 https://doi.org/10.1021/np030540k
  17. Deiter, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199 https://doi.org/10.1021/cr0200872
  18. Gaich, T.; Mulzer, J. Curr. Top. Med. Chem. 2005, 5, 1473 https://doi.org/10.2174/156802605775009793
  19. Brown, B.; Hegedus, L. S. J. Org. Chem. 2000, 65, 1865 https://doi.org/10.1021/jo9919759
  20. Burlina, F.; Favre, A.; Fourrey, J.-L. Bioorg. Med. Chem. Lett. 1997, 7, 247 https://doi.org/10.1016/S0960-894X(96)00619-1

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