CHARACTERIZATION OF 2'-DEOXYCYTIDINE AND 2'-DEOXYURIDINE ADDUCTS FORMED IN REACTIONS WITH ACROLEIN AND 2-BROMOACROLEIN

The products of the reaction of the mutagenic aldehydes, acrolein and 2-bromoacrolein, with 2'-deoxycytidine and 2'-deoxyuridine have been d etermined. These products, formed at physiological conditions, were is olated by reverse-phase HPLC and characterized by UV, H-1 NMR, fast at om bombardment MS, electrospray MS, and chemical transformation. The r eaction of 2'-deoxycytidine with acrolein and 2-bromoacrolein produced the exocyclic compounds 9-trihydro-7-hydroxypyrimido[3,4-c]pyrimidin- 2-one and 3-(2'- deoxyribosyl) o-7-hydroxy-8-bromopyrimido[3,4-c]pyrim idin-2-one, respectively. In addition to the chiral centers of deoxyri bose, one new chiral center was formed from C-1 of acrolein and two ne w chiral centers were formed from C-1 and C-2 of 2-bromoacrolein, crea ting a mixture of diastereomers for each product. These compounds are not stable in basic solution and undergo ring opening and hydrolytic d eamination, resulting in 2'-deoxyuridine adducts. The N3-alkylated 2'- deoxyuridines were also synthesized by permitting 2'-deoxyuridine to r eact with 2-bromoacrolein and acrolein. An unstable intermediate, N3-( 2''-bromo-3''-oxopropyl)-2'-deoxyuridine, was also isolated and charac terized from the reaction with 2-bromoacrolein. The reaction Of 2'-deo xyuridine with acrolein gave N3-(3''-oxopropyl)-2'-deoxyuridine as the major product, which was reduced to its corresponding alcohol with Na BH4. Reactions of 2'-deoxycytidine with 2-bromoacrolein and acrolein p roceed most rapidly at acidic or neutral pH; however, 2'-deoxyuridine reacts most rapidly at neutral or basic pH.