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

Abstract

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 degrees 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)-sulfidocyclophosphamide in nu/nu mice bearing human breast carcinoma xenografts suggested that these sulfido derivatives possess the same oncostatic efficacy as activated cyclophosphamide itself.

• Authors: G Peter, H J Hohorst
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 3 Issue 3 Pg. 181-8 ( 1979) ISSN: 0344-5704 [Print] Germany
• PMID: 527208 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cyclophosphamide

Topics

• Animals
• Antineoplastic Agents (chemical synthesis)
• Chemical Phenomena
• Chemistry
• Cyclophosphamide (analogs & derivatives, chemical synthesis, pharmacology)
• Female
• Hydrolysis
• Lethal Dose 50
• Mice
• Rats