Aldehyde-hydrate equilibrium in nucleobase 2-oxoethyl derivatives: An NMR, ESI-MS and theoretical study

N-2-oxoethyl derivatives of nucleobases are useful starting materials for the preparation of potentially active nucleoside analogues. The 1HNMR, 13CNMR, DEPT and ESI-MS spectra of adenine and thymine N-2-oxoethyl derivatives reveal that the different species in equilibrium exist mainly in two forms: aldehyde and hydrate. The NMR spectra show that the equilibrium is shifted towards the hydrate form in water-DMSO 2:1, giving equilibrium constants of 8.3 and 5.3 for adenine and thymine derivatives, respectively. ESI-MS experiments show the dependence of equilibrium shift on pH: in the case of the thymine derivative, the effect on the equilibrium is more important than in the case of the adenine derivative; this difference is explained considering different protonation sites in both structures. All assumptions are supported by theoretical calculations, which suggest the important role played by solvent in the stabilization of molecular structures and equilibrium shift. All aspects analyzed in this work are very important in order to understand the further reactivity of these nucleobase derivatives.Facultad de Ciencias Exacta

Methyltransferases: Functions and Applications

In this review the current state of the art of S-adenosylmethionine (SAM)-dependent methyltransferases and SAM are evaluated. Their structural classification and diversity is introduced and key mechanistic aspects presented which are then detailed further. Then, catalytic SAM as a target for drugs and approaches to utilise SAM as a cofactor in synthesis is introduced with different recycling approaches evaluated. The use of SAM analogues are also described. Finally O-, N-, C- and S-MTs, their synthetic applications and potential for compound diversification is given

Genetic insights into resting heart rate and its role in cardiovascular disease

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development

Exploring the Use of a Guanine-Rich Catalytic DNA for Sulfoxide Preparation.

A guanine-rich DNA oligonucleotide complexed with hemin was used to catalyze controlled oxygen transfer reactions to different sulfides for sulfoxide preparation in the presence of H2O2. Comparable activities were obtained when using fully modified L-DNA. In addition, oligonucleotide immobilization led to an active catalyst which could be successfully recovered and reused without loss of activity