Synthesis and biologic evaluation of major metabolites of N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea.
N-(2-chloroethyl)-N'-(cis-4-hydroxycylohexyl)-N-nitrosourea, a major metabolite of N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU), and its trans isomer were prepared from the corresponding 4-aminocyclohexanols. A convenient and stereospecific precursor was found in 2-oxa-3-azabicyclo[2.2.2]oct-5-ene hydrochloride, hydrogenation giving pure cis-4-aminocyclohexanol hydrochloride. The metabolites were, at nontoxic levels, at least as active as CCNU in tests against murine leukemia L1210 implanted both intraperitoneally and intracerebrally and, on a weight basis, were more active and more toxic. These observations and previously reported metabolic studies suggest that the anticancer activity of CCNU is due primarily to its metabolites.
D000818:Animals; D007939:Leukemia L1210 / Q000188:drug therapy; D008130:Lomustine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000627:therapeutic use; D051379:Mice; D009607:Nitrosourea Compounds / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D009607:Nitrosourea Compounds; D008130:Lomustine