Peter G, Hohorst H J
Cancer Chemother Pharmacol. 1979;3(3):181-8. doi: 10.1007/BF00262420.
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.
通过环磷酰胺的臭氧化反应以及中间体4-羟基环磷酰胺与各种硫醇（HSR）的反应，合成了结晶状的4-(SR)-硫代环磷酰胺，即活化环磷酰胺（4-羟基环磷酰胺）的硫代衍生物。通过元素分析、1H NMR、红外光谱和质谱对产物进行了表征。1H NMR和旋光分析表明，它们由外消旋顺式异构体组成，在室温下的结晶状态下是稳定的。在水溶液中，这些衍生物水解为4-羟基环磷酰胺和相应的硫醇，在37℃和pH 7条件下，半衰期在4至17分钟之间。发现4-(S-乙基)-和4-(S-乙醇)-硫代环磷酰胺对吉田肉瘤腹水细胞的细胞毒性以及对大鼠的毒性与活化环磷酰胺的实际毒性相同。对携带吉田腹水肉瘤的大鼠单次静脉注射4-(S-乙烷)-和4-(S-乙醇)-硫代环磷酰胺后或对携带人乳腺癌异种移植物的裸鼠单次静脉注射4-(S-乙醇)-硫代环磷酰胺后的疗效进行初步评估表明，这些硫代衍生物具有与活化环磷酰胺本身相同的抑癌功效。
