Mechanism of action of (2-haloethyl)nitrosoureas on DNA. Isolation and reactions of postulated 2-(alkylimino)-3-nitrosooxazolidine intermediates in the decomposition of 1,3-bis(2-chloroethyl)-, 1-(2-chloroethyl)-3-cyclohexyl-, and 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)-1-nitrosourea.
Three examples of the postulated but hitherto unisolated 2-(alkylimino)-3-nitrosooxazolidines (2) have been prepared containing cyclohexyl, trans-4-methylcyclohexyl, and 2-chloroethyl groups at the 2 position, respectively. These compounds correspond to intermediates previously postulated to be formed in the aqueous decomposition of the antitumor agents 1-(2-chloroethyl)-3-cyclohexyl- (CCNU), 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)- (MeCCNU), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), respectively, Compounds 2 decompose under physiological conditions to give a range of products similar to those formed from the corresponding (2-chloroethyl)nitrosoureas, including the hitherto unrecognized 2-hydroxyethl N-alkylcarbamates (9). Compounds 2a and 2b are converted with hydrochloric acid into CCNU and MeCCNU, respectively, suggesting that 2a and 2b may be reaction intermediates of decomposition. The corresponding 3-alkyl-1-nitroso-1-(2-hydroxyethyl)ureas (4) were characterized and, since they also decompose to give the same products as 2, may arise from the ring opening of 2. The intermediacy of compounds 4 can explain the formation of hydroxyethylated nucleosides isolated by other workers from the reaction of (2-chloroethyl)nitrosoureas on polynucleotides.
D000478:Alkylation; D000970:Antineoplastic Agents; D002330:Carmustine; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA; D008130:Lomustine; D009607:Nitrosourea Compounds; D012673:Semustine
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D012673:Semustine; D008130:Lomustine; D004247:DNA; D002330:Carmustine