title: X-ray crystallographic studies of cyclophosphamide (NSC-26271) derivatives.
abstract: Molecular structures of 4-hydroperoxycyclophosphamide (4-hydroperoxy-CP) and of two stereoisomers of 4-hydroperoxyisophosphamide (4-hydroperoxy-IP) have been determined by X-ray crystallography. All compounds, synthesized by Dr. A. Takamizawa by ozonolysis of appropriate open-chain precursors, demonstrate in vivo and in vitro cytotoxicity. The structure results show that for 4-hydroperoxy-CP and both isomers of 4-hydroperoxy-IP the 4-hydroperoxy group is situated axial to the ring. In 4-hydroperoxy-CP and the isomer of 4-hydroperoxy-IP which is the major product of the ozonolysis, the phosphoryl oxygen is equatorial to the ring and trans to the C4-oxygen. A scheme is presented to account for the interconversion of the two 4-hydroperoxy-IP configurations. Since a stereoisomer with a hydroperoxy or hydroxy group equatorial has not been isolated from the ozonolysis synthesis or from the Fenton oxidation of cyclophosphamide (CP), the configuration with C4-oxygen axial which is found in 4-hydroperoxy-CP and both isomers of 4-hydroperoxy-I is probably more stable and may be the configuration of 4-hydroxy compounds formed by the in vivo oxidation of CP, isophosphamide, and trophosphamide (TP). The molecular structure of TP has also been elucidated. Comparison of the conformations of the three chloroethyl alkylating groups of this molecule with those of the two chloroethyl groups of other CP derivatives indicates that these groups are highly flexible and do not assume one favored conformation.
mesh_terms: D055598:Chemical Phenomena; D002621:Chemistry; D003461:Crystallography; D003520:Cyclophosphamide / Q000031:analogs & derivatives*; D008956:Models, Chemical; D008968:Molecular Conformation; D013237:Stereoisomerism; D014961:X-Ray Diffraction
chemical_list: D003520:Cyclophosphamide