Synthesis and antitumor activity of 6 trifluoromethylcyclophosphamide and related compounds

Article abstract of DOI:10.1021/jm00245a012

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 trifluoromethyl cyclophosphamide) 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 dollowing 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 (LD₅₀330 mg/kg) was more toxic to mice than 18 (ld₅₀>500 mg/kg).