0000000000466306
AUTHOR
Raymond Grüber
Singlet Oxygen Attack on Guanine: Reactivity and Structural Signature within the B-DNA Helix
International audience; Oxidatively generated DNA lesions are numerous and versatile, and have been the subject of intensive research since the discovery of 8-oxoguanine in 1984. Even for this prototypical lesion, the precise mechanism of formation remains elusive due to the inherent difficulties in characterizing high-energy intermediates. We have probed the stability of the guanine endoperoxide in B-DNA as a key intermediate and determined a unique activation free energy of around 6 kcal mol−1 for the formation of the first C−O covalent bond upon the attack of singlet molecular oxygen (1O2) on the central guanine of a solvated 13 base-pair poly(dG-dC), described by means of quantum mechan…
Free energy profiles for two ubiquitous damaging agents: methylation and hydroxylation of guanine in B-DNA
International audience; DNA methylation and hydroxylation are two ubiquitous reactions in DNA damage induction, yet insights are scarce concerning the free energy of activation within B-DNA. We resort to multiscale simulations to investigate the attack of a hydroxyl radical and of the primary diazonium onto a guanine embedded in a solvated dodecamer. Reaction free energy profiles characterize two strongly exergonic processes, yet allow unprecedented quantification of the barrier towards this damage reaction, not higher than 6 kcal mol−1 and sometimes inexistent, and of the exergonicities. In the case of the [G(C8)-OH]˙ intermediate, we challenge the functional dependence of such simulations…
From Benzofurans to Indoles: Palladium-Catalyzed Reductive Ring-Opening and Closure via β-Phenoxide Elimination
International audience; Benzofurans can undergo ring-opening by a palladium-catalyzed process resulting in C−O bond breaking. Benzofuran-tethered 2-iodoanilines give synthetically interesting 2-(3-indolylmethyl)phenols in an overall reductive process. Mechanistic studies suggest that this unusual reaction proceeds by carbopalladation of benzofuran giving a 3-palladated 2,3-dihydrobenzofuran intermediate, which then fragments by an uncommon trans-elimination of the phenoxide group β to the metal. In this transformation, N,N-diisopropylethylamine (DIPEA) acts as a base and as a reducing agent: it regenerates palladium(0) from palladium(II), thus allowing catalytic turnover.