Synthesis of an Oligodeoxynucleotide Containing the Alkaline Labile Malondialdehyde—Deoxyguanosine Adduct Pyrimido[1,2-a]purin-10(3H)-one

摘要

Studies of the chemistry and biology of DNA damage have focused mainly on DNA adducts derived from exogenous chemicals and ultraviolet radiation. However, recent studies indicate that DNA adducts are also produced from endogenous chemicals that arise during normal metabolism, oxidative stress, etc., and that these adducts may contribute to the etiology of genetic diseases such as cancer. Malondialdehyde is a major mutagenic and carcinogenic product generated during peroxi-dation of membrane lipids that reacts with deoxynucleosides to produce a variety of adducts. The major adduct at physiological pH is 3-(2′-deoxy-β-D-erythro-pentofuranosyl)-pyrimido[1,2-a]purin-10(3H)-one (1). This adduct is also formed by reaction of malondialdehyde with single- and double-stranded DNA and recently has been identified as a constituent of liver DNA from healthy human beings. The levels of 1 in human liver represent ～5500 adducts/cell, which suggests that 1 may contribute significantly to the development of human genetic disease.