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. 1989 Dec 25;17(24):10171–10177. doi: 10.1093/nar/17.24.10171

Synthesis and evaluation of some novel phosphate and phosphinate derivatives of araA. Studies on the mechanism of action of phosphate triesters.

C McGuigan 1, J M Shackleton 1, S M Tollerfield 1, P A Riley 1
PMCID: PMC335291  PMID: 2602149

Abstract

A number of novel phosphinate and phosphate triester derivatives of the anti-viral nucleoside analogue araA have been prepared. Spectroscopic and analytical data have been collected on both the reagents and the nucleotides. An in vitro assay indicated inhibition of DNA synthesis by mammalian cells, by each of the nucleotide derivatives, in the range 3-30 microM. Inhibition was reduced, but not abolished, for the phosphinates relative to the phosphates. These results are consistent with a mode of action involving release of the free nucleoside araA and the nucleotide araAMP.

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Selected References

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  1. Bapat A. R., Zarow C., Danenberg P. V. Human leukemic cells resistant to 5-fluoro-2'-deoxyuridine contain a thymidylate synthetase with lower affinity for nucleotides. J Biol Chem. 1983 Apr 10;258(7):4130–4136. [PubMed] [Google Scholar]
  2. Bryson Y. J., Connor J. D. In vitro susceptibility of varicella zoster virus to adenine arabinoside and hypoxanthine arabinoside. Antimicrob Agents Chemother. 1976 Mar;9(3):540–543. doi: 10.1128/aac.9.3.540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chawla R. R., Freed J. J., Hampton A. Bis(m-nitrophenyl) and bis(p-nitrophenyl) esters and the phosphorodiamidate of thymidine 5'-phosphate as potential sources of intracellular thymidine 5'-phosphate in mouse cells in culture. J Med Chem. 1984 Dec;27(12):1733–1736. doi: 10.1021/jm00378a036. [DOI] [PubMed] [Google Scholar]
  4. Farquhar D., Kuttesch N. J., Wilkerson M. G., Winkler T. Synthesis and biological evaluation of neutral derivatives of 5-fluoro-2'-deoxyuridine 5'-phosphate. J Med Chem. 1983 Aug;26(8):1153–1158. doi: 10.1021/jm00362a013. [DOI] [PubMed] [Google Scholar]
  5. Farquhar D., Smith R. Synthesis and biological evaluation of 9-[5'-(2-oxo-1,3,2-oxazaphosphorinan-2-yl)-beta-D-arabinosyl]ade nine and 9-[5'-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-beta-D-arabinosyl]ade nine: potential neutral precursors of 9-[beta-D-arabinofuranosyl]adenine 5'-monophosphate. J Med Chem. 1985 Sep;28(9):1358–1361. doi: 10.1021/jm00147a043. [DOI] [PubMed] [Google Scholar]
  6. Furman P. A., Fyfe J. A., St Clair M. H., Weinhold K., Rideout J. L., Freeman G. A., Lehrman S. N., Bolognesi D. P., Broder S., Mitsuya H. Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8333–8337. doi: 10.1073/pnas.83.21.8333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. HEIDELBERGER C., SUNTHANKAR A. V., GRIESBACH L., RANDERSON S. Fluorinated pyrimidines. XII. Effects of simple nucleotides on transplanted tumors. Proc Soc Exp Biol Med. 1960 May;104:127–129. doi: 10.3181/00379727-104-25752. [DOI] [PubMed] [Google Scholar]
  8. Hunston R. N., Jones A. S., McGuigan C., Walker R. T., Balzarini J., De Clercq E. Synthesis and biological properties of some cyclic phosphotriesters derived from 2'-deoxy-5-fluorouridine. J Med Chem. 1984 Apr;27(4):440–444. doi: 10.1021/jm00370a005. [DOI] [PubMed] [Google Scholar]
  9. LEIBMAN K. C., HEIDELBERGER C. The metabolism of P32-labeled ribonucleotides in tissue slices and cell suspensions. J Biol Chem. 1955 Oct;216(2):823–830. [PubMed] [Google Scholar]
  10. LICHTENSTEIN J., BARNER H. D., COHEN S. S. The metabolism of exogenously supplied nucleotides by Escherichia coli. J Biol Chem. 1960 Feb;235:457–465. [PubMed] [Google Scholar]
  11. McGuigan C., Tollerfield S. M., Riley P. A. Synthesis and biological evaluation of some phosphate triester derivatives of the anti-viral drug AraA. Nucleic Acids Res. 1989 Aug 11;17(15):6065–6075. doi: 10.1093/nar/17.15.6065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Prusoff W. H., Goz B. Potential mechanisms of action of antiviral agents. Fed Proc. 1973 Jun;32(6):1679–1687. [PubMed] [Google Scholar]
  13. REICHARD P., SKOLD O., KLEIN G., REVESZ L., MAGNUSSON P. H. Studies on resistance against 5-fluorouracil. I. Enzymes of the uracil pathway during development of resistance. Cancer Res. 1962 Feb;22:235–243. [PubMed] [Google Scholar]
  14. Repta A. J., Rawson B. J., Shaffer R. D., Sloan K. B., Bodor N., Higuchi T. Rational development of a soluble prodrug of a cytotoxic nucleoside: preparation and properties of arabinosyladenine 5'-formate. J Pharm Sci. 1975 Mar;64(3):392–396. doi: 10.1002/jps.2600640307. [DOI] [PubMed] [Google Scholar]
  15. Schabel F. M., Jr The antiviral activity of 9-beta-D-arabinofuranosyladenine (ARA-A). Chemotherapy. 1968;13(6):321–338. doi: 10.1159/000220567. [DOI] [PubMed] [Google Scholar]

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