Reactions of 9-substituted guanines with bromomalondialdehyde in aqueous solution predominantly yield glyoxal-derived adducts

Abstract

Reactions of 9-ethylguanine, 2'-deoxyguanosine and guanosine with bromomalondialdehyde in aqueous buffers over a wide pH-range were studied. The main products were isolated and characterized by (1)H and (13)C NMR and mass spectroscopy. The final products formed under acidic and basic conditions were different, but they shared the common feature of being derived from glyoxal. Among the 1 : 1 adducts, 1,N(2)-(trans-1,2-dihydroxyethano)guanine adduct (6) predominated at pH < 6 and N(2)-carboxymethylguanine adduct (10a,b) at pH > 7. In addition to these, an N(2)-(4,5-dihydroxy-1,3-dioxolan-2-yl)methylene adduct (11a,b) and an N(2)-carboxymethyl-1,N(2)-(trans-1,2-dihydroxyethano)guanine adduct (12) were obtained at pH 10. The results of kinetic experiments suggest that bromomalondialdehyde is significantly decomposed to formic acid and glycolaldehyde under the conditions required to obtain guanine adducts. Glycolaldehyde is oxidized to glyoxal, which then modifies the guanine base more readily than bromomalondialdehyde. Besides the glyoxal-derived adducts, 1,N(2)-ethenoguanine (5a-c) and N(2),3-ethenoguanine adducts (4a-c) were formed as minor products, and a transient accumulation of two unstable intermediates, tentatively identified as 1,N(2)-(1,2,2,3-tetrahydroxypropano)(8) and 1,N(2)-(2-formyl-1,2,3-trihydroxypropano)(9) adducts, was observed.

Characterization of the Deoxyguanosine–Lysine Cross-Link of Methylglyoxal

“…Proposed mechanisms for the formation of the CE-dGuo adduct from MG-dGuo are shown in Scheme . ,,, The mechanism could potentially proceed through the ring closed MG-dGuo or through a ring-opened N 2 -dGuo adduct ( 16 ), in which the aldehyde is hydrated. Dehydration of the carbinolamine involving the N 2 -atom would provide intermediate 17 or 19 .…”

“…7,17,43,49 The mechanism can occur through a ring-opened N 2 -adduct or the ring-closed 1, N 2 -exocyclic adduct. Labeling studies are consistent with the Amadori rearrangement mechanism.…”

“…Two mechanisms for CE-dGuo formation have been proposed involving either a series of tautomerizations (Amadori rearrangement) or a 1,2-hydride shift (pinacol rearrangement) as the key step (Scheme ). ,,, The mechanism can occur through a ring-opened N 2 -adduct or the ring-closed 1, N 2 -exocyclic adduct. Labeling studies are consistent with the Amadori rearrangement mechanism.…”

Absolute configurations and stability of cyclic guanosine mono‐adducts with glyoxal and methylglyoxal

“…The structures of guanosine‐glyoxal ( G‐g ) and guanosine‐methylglyoxal ( G‐mg ) mono‐adducts have been extensively investigated using nuclear magnetic resonance spectroscopy. G‐g was confirmed to be a cyclic adduct 3‐(β‐D‐erythro‐pentofuranosyl)‐5,6,7‐trihydro‐6,7‐dihyroxy‐imidazo[1,2‐a]purine‐9‐one, 7, 11, 19–25 and a more stable compound transformed from G‐g , named N 2 ‐(carboxymethyl)‐2′‐deoxyguanosine, was recently found. 26 While G‐mg was identified as 3‐(β‐D‐erythro‐pentofuranosyl)‐5,7‐dihydro‐6,7‐dihyroxy‐6‐methyl‐imidazo[1,2‐a]purine‐9‐one in the initial reaction 21, 22, 27, 28 and then transformed to N 2 ‐(1‐carboxylethyl)‐2′‐deoxyguanosine after a longer incubation time.…”