Synthesis and antitumor activity of cyclophosphamide analogues. 3. Preparation, molecular structure determination and anticancer screening of racemic cis- and trans-4-phenylcyclophosphamide.
Cyclization of racemic 3-amino-3-phenyl-1-propranol with bis(2-chloroethyl)phosphoramidic dichloride gave a diastereomeric mixture of 4-phenylcyclophosphamide (3), which was chromatographically separated into the faster and slower eluting components. A combination of 1H/31PNMR and IR spectral data indicated that the faster and slower racemates correspond to cis-3 (mp 129-130 degrees C) and trans-3 (mp 112-114.5 degrees C), respectively. The molecular structure of the former compound was determined by X-ray crystallography and thereby unambiguously established the cis relationship between equatorially disposed phenyl and P = O substituents in a chair conformation. These results confirm the stereochemical assignments for cis- and trans-3 which have been independently deduced by Y. E. Shih, J. S. Wang, and C. T. Chen [Heterocycles, 9, 1277 (1978)]. Anticancer screening tests against L1210 lymphoid leukemia in mice have revealed that, while both diastereomers of 3 afford toxic metabolites, trans-3 led to therapeutic activity and cis-3 did not. The relevance of these findings to results reported for 4-methylcyclophosphamide and cyclophosphamide is briefly discussed.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000633:toxicity; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D014961:X-Ray Diffraction
C025046:4-phenylcyclophosphamide; D000970:Antineoplastic Agents; D003520:Cyclophosphamide