Improved Synthetic Routes to 5,8-Dideazapteroylglutamates Amenable to the Formation of Poly-γ-L-Glutamyl Derivatives

  • John B. Hynes
  • Young C. S. Yang
  • Gayle H. McCue
  • Mathew B. Benjamin
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 163)


A variety of quinazoline analogues of folic acid (5,8-dideaza-folates) are of interest as potential antineoplastic agents, biochemical probes, and/or affinity ligands for the purification of folate requiring enzymes. Chief among these are 5,8-dideazaiso-pteroylglutamate, 5,8-dideazaisoPteGlu, (IAHQ), a compound with proven activity against the growth of human colon adenocarcinoma cells in vitro, and 10-formyl-5,8-dideazapteroylglutamic acid, which serves as a substrate for glycinamide ribonucleotide transformylase and is also an effective inhibitor of mammalian thymidylate synthase. New methods for preparing these compounds in excellent purity as determined by high performance liquid chromatography (HPLC) have been developed. In each case the carboxyl groups of L-glutamic acid are protected with t-butyl ester groups, since these can subsequently be removed readily using trifluoroacetic acid without decomposition or racemization of the final product. This approach has proven to be of particular value in the formation of γ-L-glutamyl derivatives of IAHQ containing 1–3 additional glutamyl residues.


High Performance Liquid Chromatography High Performance Liquid Chromatography Reverse Phase High Performance Liquid Chromatography Significant Impurity Raney Nickel 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dunlap, R. B., Harding, N. G. L., and Huennekens, F. M., Ann. N.Y. Acad. Sci., 186, 153–165 (1971).PubMedCrossRefGoogle Scholar
  2. 2.
    Borsa, J., and Whitmore, G. F., Cancer Res., 29, 737–744 (1969).Google Scholar
  3. 3.
    Bird, O. D., Vaitkus, J. W., and Clarke, J., Mol. Pharmacol., 6, 573–575 (1970).PubMedGoogle Scholar
  4. 4.
    McCuen, R. W., and Sirotnak, F. M., Biochem. Biophys. Acta, 384, 369–380 (1975).PubMedCrossRefGoogle Scholar
  5. 5.
    Carlin, S. C., Rosenberg, R. N., VandeVenter, L., and Friedkin, M., Mol. Pharmacol., 10, 194–203 (1974).PubMedGoogle Scholar
  6. 6.
    Acharya, S. P., and Hynes, J. B., J. Heterocyclic Chem., 12, 1283–1286 (1975).CrossRefGoogle Scholar
  7. 7.
    Hynes, J. B., and Garrett, C. M., J. Med. Chem., 18, 632–634 (1975).PubMedCrossRefGoogle Scholar
  8. 8.
    Oatis, J. E., Jr., Hynes, J. B., J. Med. Chem., 20, 1393–1396 (1977).PubMedCrossRefGoogle Scholar
  9. 9.
    Scanlon, K. J., Moroson, B. A., Bertino, J. R., and Hynes, J. B., Mol. Pharmacol., 16, 261–269 (1979).PubMedGoogle Scholar
  10. 10.
    Rode, W., Scanlon, K. J., Hynes, J. B., and Bertino, J. R., J. Biol. Chem., 254, 11538–11543 (1979).PubMedGoogle Scholar
  11. 11.
    Smith, G. K., Mueller, W. T., Benkovic, P. A., and Benkovic, S. J., Biochemistry, 20, 1241–1245 (1981).CrossRefGoogle Scholar
  12. 12.
    Jones, T. R., Calvert, A. H., Jackman, A. L., Brown, S. J., Jones, M., and Harrap, K. R., Eur. J. Cancer, 17, 11–19 (1981).PubMedCrossRefGoogle Scholar
  13. 13.
    Fernandes, D. J., Cardenas, R. M., Hynes, J. B., and Bertino, J. R., The Pharmacologist, 22, 176 (1980).Google Scholar
  14. 14.
    Tsang, K. T., Hynes, J. B., and Fudenberg, H. H., Chemotherapy, in press (1982).Google Scholar
  15. 15.
    McGuire, J., Hsieh, P., and Bertino, J. R. (unpublished results).Google Scholar
  16. 16.
    Hynes, J. B., Eason, D. E., Garrett, C. M., Colvin, P. L., Jr., Shores, K. E., and Freisheim, J. H., J. Med. Chem., 20, 588–591 (1977).PubMedCrossRefGoogle Scholar
  17. 17.
    Kajtar, M., and Hollosi, M., Acta, Chim. Acad. Sci. Hung., 65, 403–432 (1970).Google Scholar
  18. 18.
    Kovacs, J., Schmidt, G. M., and Ghatar, U. R., Biopolymers, 6, 817–836 (1968).PubMedCrossRefGoogle Scholar
  19. 19.
    Meienhofer, J., Jones, P. M., Godwin, H. A., and Rosenberg, I. H., J. Org. Chem., 35, 4137–4140 (1970).PubMedCrossRefGoogle Scholar
  20. 20.
    Davoll, J., and Johnson, A. M., J. Chem. Soc. (C), 977–1002 (1970).Google Scholar
  21. 21.
    Gordon, M., Ravel, J. M., Eakin, R. E., and Shive, W., J. Am. Chem. Soc, 70, 878–879 (1948).PubMedCrossRefGoogle Scholar
  22. 22.
    Priest, D. G., Hynes, J. B., Jones, C. W., and Ashton, W. T., J. Pharm. Sci., 63, 1158–1160 (1974).PubMedCrossRefGoogle Scholar
  23. 23.
    Cashmore, A. R., Dreyer, R. N., Horvath, C., Knipe, J., Coward, J. K., and Bertino, J. R., Methods in Enzymology, 66, 459–468 (1980).PubMedCrossRefGoogle Scholar
  24. 24.
    Fernandes, D. J., Cardenas, R. M., Bertino, J. R., and Hynes, J. B., (1981) (this text).Google Scholar

Copyright information

© Springer Science+Business Media New York 1983

Authors and Affiliations

  • John B. Hynes
    • 1
  • Young C. S. Yang
    • 1
    • 2
  • Gayle H. McCue
    • 1
  • Mathew B. Benjamin
    • 1
  1. 1.Department of Pharmaceutical Chemistry College of PharmacyMedical University of South CarolinaCharlestonUSA
  2. 2.College of Graduate StudiesMedical University of South CarolinaUSA

Personalised recommendations