DNA Guanine Adducts from 3-Methyl-1,2,3-oxadiazolinium Ions

Abstract

The reaction of 3-methyl-1,2,3-oxadiazolinium tosylate 10, a close model for a putative reactive intermediate in the carcinogenic activation of ethanol nitrosamines such as (2-hydroxyethyl)methylnitrosamine 1, with various guanine derivatives, including acycloguanosine 12, deoxyguanosine, deoxyguanosine monophosphate, and cyclic guanosine monophosphate, various DNA oligomers, and calf-thymus DNA has been examined to determine whether this compound methylates and hydroxyethylates guanine residues as proposed. In all of the transformations, 7-(2-(methylnitrosamino)ethyl)guanine (14) is the major product, following acidic hydrolysis, and exceeds the formation of 7-methylguanine by ratios ranging from 4:1 to 48:1, depending upon the guanine bearing substrate. O 6-(2-(Methylnitrosamino)ethyl)deoxyguanosine (20) was prepared from the Mitsunobu coupling of 1 and a protected deoxyguanosine derivative. 20 is not produced in the reaction of 10 and deoxyguanosine and decomposes to 1 and guanine upon mild acid treatment, suggesting possible neighboring group participation in its facile hydrolytic cleavage. All of the major products from the reaction of 10 and 12 have been characterized, including the direct alkylation product, 7-(2-(methylnitrosamino)ethyl)acycloguanosine (13), and N 2-(2-(methylnitrosamino)ethyl)guanine, which was independently synthesized. Elucidation of the reactions of DNA with 10 and other electrophiles was facilitated by the development of both partial and total enzymatic hydrolysis assays utilizing 32P-5‘-labeled DNA oligotetramers containing one of each base type and HPLC with radiometric detection. The partial hydrolysis assay gives information as to the type of base being modified, and the total hydrolysis assay permits a determination of the number of adducts produced for a given base. The assays permit a comparison between reactions where the same type of base adduct could be expected. Comparisons of the reactions of ethylene oxide and 10 using this methodology showed that 10 does not hydroxyethylate guanine in DNA.

Comparative theoretical investigation of the formation of DNA interstrand crosslinks induced by two kinds of N‐nitroso compounds: nitrosoureas and nitrosamines

“…The low relative energy of 8 (−11.4 kcal/mol) suggests that it may be reasonably stable. It has been demonstrated in experimental and theoretical studies that 1,2,3‐oxadiazolinium can directly alkylate DNA and results in various guanine derivatives . From the optimized structure of 8 , it can be seen that the Mulliken charges (with hydrogen summed into heavy atoms) on the C β atom (0.342) are obviously higher than those on the C α atom (0.243) and the APT charges on C β atom (0.523) are also higher than those on the C α atom (0.345).…”

4,5‐Dihydro‐1,2,3‐oxadiazole: A Very Elusive Key Intermediate in Various Important Chemical Transformations

“…However, 1 or its decay products were not even mentioned in this case. There are also a few reports5c,d, 12 doubting the role of 2 as a methylating agent. The structure of 2 is an intriguing one and cannot be fully assigned by NMR spectroscopy alone.…”

Relationship between the molecular structure and the anticancer activity of N‐(2‐chloroethyl)‐N′‐cyclohexyl‐N‐nitrosoureas: A theoretical investigation

“…Because the anchimeric assistant reaction is a competitive mechanism with the retro‐ene reaction, the decomposition via pathway 1, which is believed to be the main process for the anticancer activity of CENUs, will be consequently inhibited by the decrease of B O1Cl8 . The researches57–59 on the carcinogenesis of nitrosamine presented evidences that the β‐metabolites of the carcinogenic nitrosamines underwent the anchimeric assistant process to form 4,5‐dihydro‐1,2,3‐oxadiazolium, which was capable of alkylating cellular targets and initiating the carcinogenesis. However, it has not been fully understood that whether the anchimeric assistant process is related to the carcinogenic side effect of CCNU and other anticancer nitrosoureas.…”