Synthesis and antitumor activity of analogues of ifosfamide modified in the N-(2-chloroethyl) group.
A series of 3-(2-chloroethyl)-N-(2-X-ethyl)tetrahydro-2H-1,3,2-oxazaphosphorin -2-amine 2-oxides with various X substituents have been prepared by cyclization of racemic ifosfamide or its enantiomers with sodium hydride and subsequent treatment of intermediary products with hydrobromic acid, diethyl hydrogen phosphate, dibenzyl hydrogen phosphate, p-toluenesulfonic acid, and acetic acid. All of these compounds were tested in vivo against L 1210 lymphoid leukemia in mice. Only bromo analogue 13 and its enantiomers were effective, exceeding the activity of racemic ifosfamide and cyclophosphamide. The therapeutic index of the racemic 13 and its levorotatory enantiomer was about 1.7 times higher than that for ifosfamide and about 2.7 times higher than that for cyclophosphamide.
Misiura
K
K
Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Boczna.
Kinas
R W
RW
Stec
W J
WJ
Kusnierczyk
H
H
Radzikowski
C
C
Sonoda
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D003520:Cyclophosphamide / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D007202:Indicators and Reagents; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008815:Mice, Inbred Strains; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D003520:Cyclophosphamide; D007069:Ifosfamide