Synthesis and antitumor activity of 6-trifluoromethylcyclophosphamide and related compounds.
In an attempt to increase the combined toxicity of the metabolic end-products [acrolein (4) and phosphoramide mustard (3)] from cyclophosphamide (1), the analog 2-[bis(2-chloroethyl)amino]tetrahydro-6-trifluoromethyl-2H-1,3,2-oxazaphosphorine 2-oxide (2, 6-trifluoromethylcyclophosphamide) was synthesized and its metabolism and antitumor activity studied. Following metabolism of 2 by rat liver microsomes the predicted formation of 4,4,4-trifluorocrotonaldehyde (5) was confirmed by isolation and identification, by mass spectrometry, of its dinitrophenylhydrazone. The therapeutic indices (LD50-/ID90) for 2 against the ADJ/PC6 mouse tumor and the Walker 256 tumor in the rat were 28.6 and 7.7, respectively, and were lower than the corresponding values for 1 (91.8 and 33.2, respectively) although the toxicities toward Walker cells in a bioassay system of 1 and 2 following microsomal metabolism were similar. In order to study the toxicities of 4 and 5 released under drug metabolizing conditions independently of the production of a toxic mustard the analogs 18 [2-(diethylamino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide] and 6 [2-(diethylamino)tetrahydro-6-trifluoromethyl-2H-1,3,2-oxazaphosphorine 2-oxide] were also synthesized. The release of 5 from 6 following metabolism was confirmed and shown by use of the bioassay system to be an event of similar toxicity to release of 4 from 18; in vivo, however, 6 (LD50 330 mg/kg) was more toxic to mice than 18 (LD50 greater than 500 mg/kg).
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D002279:Carcinoma 256, Walker / Q000188:drug therapy / Q000378:metabolism; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010954:Plasmacytoma / Q000188:drug therapy; D051381:Rats
D000970:Antineoplastic Agents; D003520:Cyclophosphamide