Fluorinated analogues of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea: an attempt to control metabolism

In seeking to block and thereby determine the role of the rapid in vivo hydroxylation of the cyclohexyl moiety of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in relation to antitumor activity and tissue distribution, the 3-(1H-decafluorocyclohexyl) analogue (FCCNU) was synthesized. FCCNU showed marked toxicity and little activity against the intracerebral L1210 leukemia in mice. At pH 7 in phosphate buffer at room temperature FCCNU rapidly decomposed to give 1-(1H-decafluorocyclohexyl)-3-nitrosoimidazolidin-2-one (3) and thence, by loss of HF, the 1-(nonafluorocyclohexenyl) derivative (4); CCNU did not follow this decomposition pathway to any significant extent. Both 3 and 4 were unstable in the buffer, but each was isolated crystalline and characterized. The formation of 3 and 4 account for the biological properties of FCCNU.