Investigation of 6-thiodeoxyguanosine alkylation products and their role in the potentiation of BCNU cytotoxicity.
The principal products of the reaction of 6-thio-2'-deoxyguanosine (6-TdGuo) with dimethylsulfate are S6-methyl-6-thiodeoxyguanosine and 7-methyl-6-thiodeoxyguanosine, identified by ultraviolet and mass spectrometry. To study the reactions of 6-TdGuo in DNA, cells were treated with 6-thioguanine, which is incorporated into DNA during S-phase; DNA was purified from cell lysates and reacted with 3H-methylnitrosourea. In addition to the expected methylated purines (O6-methylguanine, 7-methylguanine and 3-methyladenine), 0.6% of the total product was S6-methyl-6-thioguanine. On the basis of thioguanine content, the formation of S6-methyl-6-thioguanine occurs 70-fold more efficiently than O6-methylguanine, which indicates that 6-thioguanine incorporated into DNA is very susceptible to chemical modification by alkylating agents. The ultraviolet and mass spectra of two of the major products of the reaction between 6-TdGuo and 2-chloroethyl methanesulfonate suggest that the structures are (1,S6-ethano)-6-thiodeoxyguanosine and (S6,7-ethano)-6-thiodeoxyguanosine, which are presumably formed by an internal cyclization reaction that proceeds through a sulfonium ion intermediate. In cells, this intermediate could react with DNA nucleophiles to form both DNA intra- and interstrand cross-links.
D000478:Alkylation; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002330:Carmustine / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents; D004249:DNA Damage; D004273:DNA, Neoplasm; D003854:Deoxyribonucleotides; D006151:Guanosine / Q000031:analogs & derivatives*; D008770:Methylnitrosourea; D013056:Spectrophotometry, Ultraviolet; D013463:Sulfuric Acid Esters; D013866:Thioguanine / Q000031:analogs & derivatives; D013872:Thionucleosides
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D003854:Deoxyribonucleotides; D013463:Sulfuric Acid Esters; D013872:Thionucleosides; D006151:Guanosine; D008770:Methylnitrosourea; C005783:6-thioguanosine; D013866:Thioguanine; C007482:dimethyl sulfate; D002330:Carmustine