Synthesis and antitumor activity of cyclophosphamide analogues. 3. Preparation, molecular structure determination and anticancer screening of racemic cis- and trans-4-phenylcyclophosphamide

J Med Chem. 1980 Apr;23(4):372-5. doi: 10.1021/jm00178a005.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / toxicity
  • Cyclophosphamide / analogs & derivatives*
  • Cyclophosphamide / chemical synthesis
  • Cyclophosphamide / pharmacology
  • Cyclophosphamide / toxicity
  • Female
  • Leukemia L1210 / drug therapy
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Stereoisomerism
  • X-Ray Diffraction

Substances

  • 4-phenylcyclophosphamide
  • Antineoplastic Agents
  • Cyclophosphamide