Reaction of trans-4- N-acetoxy- N-acetylaminostilbene with guanosine and deoxyguanosine in vitro: The primary reaction product at N2 of guanine yields different final adducts

Abstract

The model ultimate carcinogen, trans-4- N-acetoxy- N-acetylaminostilbene ( N-acetoxy-AAS), was reacted with guanosine (Guo) and deoxyguanosine (d-Guo) and the resulting adducts were purified by Sephadex LH-20 chromatography and HPLC for structure identification. A number of new adducts was identified by mass and 1H-NMR spectroscopy. The generation of all known adducts can now be explained by a common mechanism. The electrophile formed from the hydroxamic acid ester at C-β reacts in a first step predominantly with N 2 of guanine (Gua). The resulting quinone-imide intermediate reacts in a second step with either one of three nucleophiles: (1) predominantly with N3 of Gua to yield the previously described angular cyclic adducts ((5 R,6 R)/(5 S,6 S)-9-oxo-5,6,7,9-tetrahydroimidazo(2,1-b)purines); (2) with N1 of Gua to yield linear cyclic adducts ((6 R,7 R)/(6 S,7 S)-9-oxo-5,6,7,9-tetrahydro-imidazo(1,2-a)purines); (3) with water to yield the open ring (1 R,2 R)/(1 S,2 S)-2-( N 2′-guanyl)-1-hydroxyethanes. To some minor extent (1 : 8–1 : 9) the electrophile reacts first with N1 or N3 of guanine which leads to the formation of two pairs of the corresponding regioisomeric cyclic adducts. This reaction mechanism may also explain the formation of cross-links between different bases.