Activated cyclophosphamide anticancer drugs: molecular structures of cis- and trans-4-hydroperoxyisophosphamides

• Published in: Journal of medicinal chemistry 1983-05, Vol.26 (5), p.679-683
• Main Authors: Camerman, Arthur, Smith, H. Warren, Camerman, Norman
• Format: Article
• Language: English
• Subjects: Chemical Phenomena; Chemistry; Cyclophosphamide - analogs & derivatives; Ifosfamide - analogs & derivatives; Isomerism; Models, Molecular; X-Ray Diffraction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00359a011

Molecular structures of two stereoisomers of 4-hydroperoxyisophosphamide (HPIPA) have been determined by single-crystal X-ray diffraction. These isomers are active cytostatic agents closely related to an active metabolite of the antitumor drug isophosphamide, an analogue of cyclophosphamide. Both isomers crystallize in monoclinic space group P21/c with cell dimensions for cis-HPIPA of a = 8.999 (2), b = 8.743 (2), c = 17.078 (4) A; beta = 107.91 (2) degrees, and Z = 4 molecules per unit cell, and cell dimensions for trans-HPIPA of a = 15.184 (3), b = 10.345 (3), c = 18.205 (3) A, beta = 114.15 (1) degrees, and Z = 8. The structures were solved by direct methods and refined by anisotropic least squares to a discrepancy index R = 0.048 for cis-HPIPA and R = 0.065 for trans-HPIPA. In both isomers the 4-hydroperoxy group is situated axial to the ring. The phosphoryl oxygen atom is situated axial to the ring and, thus, cis to the C(4) oxygen in the cis-HPIPA isomer. In the trans-HPIPA isomer, the phosphoryl oxygen is equatorial to the ring and trans to the C(4) oxygen.