A novel synthesis of malondialdehyde adducts of deoxyguanosine, deoxyadenosine, and deoxycytidine

Malondialdehyde (MDA) is a mutagenic product of lipid peroxidation and prostaglandin biosynthesis. MDA reacts with DNA bases to produce adducts of deoxyguanosine (M(1)G), deoxyadenosine (M(1)A), and deoxycytidine (M,C). A novel synthesis of these MDA nucleoside adducts has been developed, which significantly improves their availability. For the deoxyguanosine adduct, M(1)G, an amine equivalent to MDA, 4-amino-3-(phenylselenyl)butane-1,2-diol, was reacted with 2-fluoro-O-6-(2-(trimethylsilyl)ethyl)-2'-deoxyinosine via a nucleophilic aromatic substitution reaction followed by acid hydrolysis of the O-6-protecting group to give an N-2-modified deoxyguanosine intermediate. Periodate oxidation of this intermediate under slightly acidic conditions gave M(1)G in good overall yield via cleavage of the vicinal diol unit and concomitant oxidation of the phenylselenide group to the corresponding selenoxide and syn beta-elimination. M(1)A and MIC were synthesized by the same strategy starting from 6-chloropurine 2'-deoxyriboside and 1-(2-deoxy-beta-D-erythro-pentofuranosyl)-4-(1H-1,2,4-triazol-1-yl)-2-(1H)pyrimidinone, respectively. An advantage of this approach is that similar chemistry has been shown to be directly applicable to the synthesis of site specifically adducted oligonucleotides containing activated nucleobases such as those used in this study. This strategy may offer an improved synthesis to oligonucleotides containing M(1)G and a feasible approach to M(1)A and M1C containing oligonucleotides.