Skip to main content
SpringerLink
Log in

Synthesis and preliminary antitumor evaluation of 4-(SR)-sulfido-cyclophosphamides

  • Original Articles
  • 4-(SR)-Sulfido-Cyclophosphamide
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Summary

Crystalline 4-(SR)-sulfidocyclophosphamides, sulfido derivatives of activated cyclophosphamide (4-hydroxycyclophosphamide), were synthesized by ozonation of cyclophosphamide and reaction of the intermediate 4-hydroxycyclophosphamide with various thiols (HSR). The products were characterized by elemental analysis, 1H NMR and IR spectroscopy, and mass spectrometry. 1H NMR and polarimetric analysis demonstrated that they consist of racemic cis-isomers that are stable in the crystalline state at room temperature. In aqueous solution these derivatives are hydrolyzed to 4-hydroxycyclophosphamide and the corresponding thiol, with half-lives ranging between 4 and 17 min at 37° C and pH 7. The cytotoxicity of 4-(S-ethyl)-and 4-(S-ethanol)-sulfidocyclophosphamide against Yoshida sarcoma ascites cells and the toxicity in rats were found to be practically identical with those of activated cyclophosphamide. A preliminary evaluation of the curative effect after a single IV injection of 4-(S-ethane)-and 4-(S-ethanol)-sulfidocyclophosphamide in rats bearing Yoshida ascites sarcoma or of 4-(S-ethanol)-sulfidocyclophsphamide in nu/nu mice bearing human breast carcinoma xenografts suggested that these sulfido derivatives possess the same oncostatic efficacy as activated cyclophosphamide itself.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Benckhuysen, C., Van der Steen, J., Spanjersberg, J.: Two stable Fenton oxidation products of cyclophsophamide (NSC-26271) as precursors of 4-hydroxycyclophosphamide (NSC-196562) under physiological conditions. Cancer Treat. Rep. 60 (4), 369–372 (1976)

    Google Scholar 

  2. Brock, N.: Comparative pharmacologic study in vitro and in vivo with cyclophosphamide (NSC-26271), cyclophosphamide metabolites, and plain nitrogen mustard compounds. Cancer Treat. Rep. 60 (4), 301–308 (1976)

    Google Scholar 

  3. Brock, N., Hohorst, H.-J.: Über die Aktivierung von Cyclophosphamid in vivo und in vitro. Arzneim.-Forsch. 13, 1021–1031 (1963)

    Google Scholar 

  4. Brock, N., Hohorst, H.-J.: The problem of specificity and selectivity of alkylating cytostatics: Studies on N-2-chloroethylamido-oxazaphosphorines. Z. Krebsforsch. 88, 185–215 (1977)

    Google Scholar 

  5. Chargaff, E., Levine, C., Green, C.: Techniques for the demonstration by chromatography of nitrogenous lipid constituents, sulfur-containing amino acids, and reducing sugars. J. Biol. Chem. 175, 67–71 (1948)

    Google Scholar 

  6. Connors, T. A., Cox, P. J., Farmer, P. B., Foster, A. B., Jarman, M.: Some studies of the active intermediates formed in the microsomal metabolism of cyclophosphamide and isophosphamide. Biochem. Pharmacol. 23, 115–129 (1974)

    Google Scholar 

  7. Draeger, U., Peter, G., Hohorst, H.-J.: Deactivation of cyclophosphamide (NSC-26271) metabolites by sulfhydril compounds. Cancer Treat. Rep. 60 (4), 355–359 (1976)

    Google Scholar 

  8. Egan, W., Zon, G.: High resolution 1H and 13C-NMR investigations of cyclophosphamide conformational mobility. Tetrahedron Letters 11, 813–816 (1976)

    Google Scholar 

  9. Friedman, O. M., Boger, E.: Colorimetric estimation of nitrogen mustards in aqueous media. Anal. Chem. 33, 906–910 (1961)

    Google Scholar 

  10. Hohorst, H.-J., Draeger, U., Peter G., Voelcker, G.: The problem of oncostatic specificity of cyclophosphamide (NSC-26271): Studies on reactions that control the alkylating and cytotoxic activity. Cancer Treat. Rep. 60 (4), 309–315 (1976)

    Google Scholar 

  11. Hohorst, H.-J., Peter, G., Struck, R. F.: Synthesis of 4-hydroperoxy derivatives of ifosfamide and trofosfamide by direct ozonation and preliminary antitumor evaluation in vivo. Cancer Res. 36, 2278–2281 (1976)

    Google Scholar 

  12. Karplus, M.: Vicinal proton coupling in nuclear magnetic resonance. J. Am. Chem. Soc. 85, 2870–2871 (1963)

    Google Scholar 

  13. Lenssen, U.: Untersuchungen über die Reaktion von 4-Hydroxycyclophosphamid mit Thiol-Verbindungen und über die Aufnahme von Cyclophosphamid und seinen Metaboliten in Tumorzellen. Ph.D. Dissertation, University of Frankfurt/M., 1976

  14. Peter, G.: Synthese von cancerotoxischen N-(2-Chloräthyl)-2-amino-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxid-Derivaten und Untersuchungen zu ihrer Struktur und Chemie. Ph.D. Dissertation, University of Frankfurt/M., 1977

  15. Peter, G., Wagner, T., Hohorst, H.-J.: Studies on 4-hydroperoxycyclophosphamide (NSC-181815): A simple preparation method and its application for the synthesis of a new class of “activated” sulfur-containing cyclophosphamide (NSC-26271) derivatives. Cancer Treat. Rep. 60 (4), 429–435 (1976)

    Google Scholar 

  16. Przybylski, M., Ringsdorf, H., Voelcker, G., Draeger, U., Peter, G., Hohorst, H.-J.: Characterization of cyclophosphamide (NSC-26271) metabolites and related derivatives by field-desorption and electron-impact mass spectrometry. Cancer Treat. Rep. 60 (4), 509–516 (1976)

    Google Scholar 

  17. Przybylski, M., Ringsdorf, H., Lenssen, U., Peter, G., Voelcker, G., Wagner, T., Hohorst, H.-J.: Mass spectrometric characterization of activated N-(2-chloroethyl) amido oxazaphosphorine derivatives. Biomed. Mass Spectrom. 4 (4), 209–215 (1977)

    Google Scholar 

  18. Schmähl, D., Druckrey, H.: Contributions to the mode of action of N-oxide of nitrogen mustard. Naturwissenschaften 43, 199–203 (1956)

    Google Scholar 

  19. Sober, H. A. (ed.): Ionization constants of acids and basesthiol. In: Handbook of biochemistry, 2nd ed., p. J-223. Cleveland, Ohio: The Chemical Rubber Co. 1970

    Google Scholar 

  20. Takamizawa, A., Matsumoto, S., Iwata, T., Katagiri, K., Tochino, Y., Yamaguchi, K.: Studies on cyclophosphamide metabolites and their related compounds. II. Preparation of an active species of cyclophosphamide and some related compounds. J. Am. Chem. Soc. 95 (3), 985–986 (1973)

    Google Scholar 

  21. Takamizawa, A., Matsumoto, S., Iwata, T., Tochino, Y., Katagiri, K., Yamaguchi, K., Shiratori, O.: Synthesis and metabolic behavior of the suggested active species of isophosphamide having cytostatic activity. J. Med. Chem. 17, 1237–1239 (1974)

    Google Scholar 

  22. Takamizawa, A., Matsumoto, S., Iwata, T., Makino, I.: Synthesis, stereochemistry and antitumor activity of 4-hydroperoxyisophosphamide (NSC-227114) and related compounds. Chem. Pharm. Bull. (Tokyo) 25 (8) 1877–1891 (1977)

    Google Scholar 

  23. Voelcker, G., Draeger, U., Peter, G., Hohorst, H.-J.: Studien zum Spontanzerfall von 4-Hydroxycyclophosphamid und 4-Hydroperoxycyclophosphamid mit Hilfe der Dünnschichtchromatographie. Arzneim.-Forsch. 24 (8), 1172–1176 (1974)

    Google Scholar 

  24. Voelcker, G. Giera, H. P., Hohorst, H.-J.: Zur Bindung von Cyclophosphamid und Cyclophosphamid-Metaboliten an Serum-Albumin. Z. Krebsforsch. 91, 127–142 (1978)

    Google Scholar 

  25. Voelcker, G., Häglsperger, R., Hohorst, H.-J.: Fluorometrische Bestimmungen von “aktiviertem” Cyclophosphamid und Ifosfamid im Blut. J. Cancer Res. Clin. Oncol. 93, 233–240 (1979)

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Gustav-Embden-Zentrum der Biologischen Chemie der Universität Frankfurt am Main, Theodor-Stern-Kai 7, D-6000, Frankfurt am Main 70, Federal Republic of Germany

    G. Peter & H.-J. Hohorst

Authors
  1. G. Peter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H.-J. Hohorst
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peter, G., Hohorst, HJ. Synthesis and preliminary antitumor evaluation of 4-(SR)-sulfido-cyclophosphamides. Cancer Chemother. Pharmacol. 3, 181–188 (1979). https://doi.org/10.1007/BF00262420

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00262420

Keywords

Search

Navigation