Mechanism of action of the nitrosoureas—V

Add time:07/23/2019    Source:sciencedirect.com

DNA which has been exposed to 2-haloethylnitrosoureas has been shown to contain the chemical crosslink 1-(N3-deoxycytidyl), 2-(N1-deoxyguanosinyl)-ethane [W.P. Tong, M.C. Kirk and D.B. Ludlum, Cancer Res. 43, 3102 (1982)]. We have hypothesized that this structure is formed by an initial attack of a 2-haloethyl group on the 6 position of guanine followed by an intramolecular rearrangement and secondary crosslinking reaction with cytosine. We have now shown that DNA which had been reacted with N-(2-fluoroethyl)-N′-cyclohexyl-N-nitrosourea contained O6-(2-fluoroethyl) guanine and have thus demonstrated that the first step in the proposed mechanism occurs. Furthermore, O6-(2-fluoroethyl)guanosine hydrolyzed to N1-(2-hydroxyethyl)guanosine, showing that the necessary intramolar rearrangement occurs. These two observations greatly strengthen the proposed route to DNA crosslinking by the 2-haloethylnitrosoureas.

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