Synthesis of C-ribosyl 1,2,4-triazolo[3,4-f[hair space][hair space]][1,2,4]triazines as inhibitors of adenosine and AMP deaminases

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Philip J. Dudfield, Van-Duc Le, Stephen D. Lindell and Charles W. Rees


Abstract

Modified C-nucleosides and nucleotides with an enhanced tendency to undergo covalent hydration are of interest as potential inhibitors of adenosine deaminase (ADA) and AMP deaminase, respectively. In a search for such compounds we have synthesized 6-dimethylamino-3-(β-D-ribofuranosyl)-1,2,4-triazolo[3,4-f[hair space][hair space]][1,2,4]triazine 4 in four steps (42% overall yield) from the readily available allonic acid 6 and the hydrazine 7. The hydrazide 16 derived from 6 and 7 (78%) is converted directly into the cyclised chloro compound 19 (62%) with phosphorus trichloride oxide, followed by dechlorination (96%) and deprotection (90%). Riboside 4 undergoes partial hydration in water to the covalent hydrate 22, and is a modest inhibitor of mammalian ADA (IC50 180 µM).


References

  1. P. J. Dudfield, V.-D. Le, S. D. Lindell and C. W. Rees, J. Chem. Soc., Perkin Trans. 1, 1999, 2929 RSC.
  2. C. G. Earnshaw, AgrEvo UK Ltd, unpublished results. Further details of our calculations can be found in V.-D. Le, Ph.D. Thesis, University of London, 1997, p. 26and in S. D. Lindell, B. A. Moloney, B. D. Hewitt, C. G. Earnshaw, P. J. Dudfield and J. E. Dancer, Bioorg. Med. Chem. Lett., 1999, 9, 1985 Search PubMed See also M. D. Erion and M. R. Reddy, J. Am. Chem. Soc., 1998, 120, 3295 Search PubMed.
  3. H. K. Han, J. C. Lee, Y. H. Kang, J.-H. Kim and D. Y. Chi, Synth. Commun., 1992, 22, 2815 CAS.
  4. L. Kalvoda, J. Carbohydr. Nucleosides, Nucleotides, 1976, 3, 47 Search PubMed.
  5. W. W. Paudler and T.-K. Chen, J. Heterocycl. Chem., 1970, 7, 767 CAS; H. Neunhoeffer and B. Lehmann, Chem. Ber., 1976, 109, 1113 CAS.
  6. B. T. Keen, R. J. Radel and W. W. Paudler, J. Org. Chem., 1977, 42, 3498 CrossRef CAS; R. J. Radel, J. L. Atwood and W. W. Paudler, J. Org. Chem., 1978, 43, 2514 CrossRef CAS.
  7. C. A. Lovelette, J. Heterocycl. Chem., 1979, 16, 555 CAS.
  8. Y. Kang, S. B. Larson, R. K. Robins and G. R. Revankar, J. Med. Chem., 1989, 32, 1547 CrossRef CAS.
  9. L. J. S. Knutsen, B. D. Judkins, W. L. Mitchell, R. F. Newton and D. I. C. Scopes, J. Chem. Soc., Perkin Trans. 1, 1984, 229 RSC.
  10. K. Ramasamy, B. G. Ugarkar, P. A. McKernan, R. K. Robins and G. R. Revankar, J. Med. Chem., 1986, 29, 2231 CrossRef CAS.
  11. P. D. Cook and D. J. McNamara, J. Heterocycl. Chem., 1986, 23, 155 CAS.
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