Formation of cyclic adducts in nucleic acids by the haloethylnitrosoureas.
The haloethylnitrosoureas react with adenine and cytosine nucleosides in aqueous solution at neutral pH to form 1,N6-ethanoadenine and 3,N4-ethanocytosine nucleosides, respectively. These cyclic nucleosides probably result from a two-step reaction in which a haloethyl group first attaches to the ring nitrogen and then reacts with the exocyclic amino group. They are relatively stable at neutral pH, and can be formed in both DNA and synthetic polynucleotides. Since the base-pairing positions are affected, the presence of these modified nucleosides in DNA would presumably change the informational content of this molecule, leading to mutagenic or cytotoxic effects. Haloethyl groups can also attack the O6 position of guanine nucleosides. Attempts to synthesize O6-chloroethylguanine nucleosides have not yet been successful, but O6-fluoroethylguanosine has been fully characterized. This compound undergoes a base-catalysed hydrolysis to 1-hydroxyethylguanosine in aqueous solution at 37 degrees C, evidently through the cyclic intermediate, 1,O6-ethanoguanosine. This intermediate can be isolated by high-performance liquid chromatography and has been partially characterized by ultraviolet spectrometry. We have hypothesized that the corresponding 1,O6-ethanoguanine deoxynucleoside is formed in DNA by rearrangement of O6-haloethyldeoxyguanosine, and that this cyclic nucleoside is an intermediate in the formation of the DNA cross-link, 1-(3-deoxycytidyl),2-(1-deoxyguanosinyl) ethane. The formation of this cross-link in DNA probably explains some of the antitumour activity of the haloethylnitrosoureas. A similar mechanism may lead to cross-links between deoxyadenosine and thymidine.
D000225:Adenine / Q000031:analogs & derivatives*; D055598:Chemical Phenomena; D002621:Chemistry; D003562:Cytidine / Q000031:analogs & derivatives*; D003596:Cytosine / Q000031:analogs & derivatives*; D004249:DNA Damage; D005038:Ethylnitrosourea / Q000031:analogs & derivatives*; D006151:Guanosine / Q000031:analogs & derivatives*
C051141:1,N(6)-ethanoadenine; C051144:3,N(4)-ethanocytidine; C051142:1,O(6)-ethanoguanosine; D006151:Guanosine; C051143:3,N(4)-ethanocytosine; D003562:Cytidine; D003596:Cytosine; D000225:Adenine; D005038:Ethylnitrosourea