Green synthesis of triazolo-nucleoside conjugates via azide–alkyne C–N bond formation

Modified nucleosides are the core precursors for the synthesis of artificial nucleic acids, and are important in the field of synthetic and medicinal chemistry. In order to synthesize various triazolo-compounds, copper and ruthenium catalysed azide–alkyne 1,3-dipolar cycloaddition reactions also known as click reaction have emerged as a facile and efficient tool due to its simplicity and convenient conditions. Introduction of a triazole ring in nucleosides enhances their therapeutic value and various photophysical properties. This review primarily focuses on the plethora of synthetic methodologies being employed to synthesize sugar modified triazolyl nucleosides, their therapeutic importance and various other applications.

Circadian and chemotherapy-related changes in urinary modified nucleosides excretion in patients with metastatic colorectal cancer

Urinary levels of modified nucleosides reflect nucleic acids turnover and can serve as non-invasive biomarkers for monitoring tumour circadian dynamics, and treatment responses in patients with metastatic colorectal cancer. In 39 patients, median overnight urinary excretion of LC-HRMS determinations of pseudouridine, was ~ tenfold as large as those of 1-methylguanosine, 1-methyladenosine, or 4-acetylcytidine, and ~ 100-fold as large as those of adenosine and cytidine. An increase in any nucleoside excretion after chemotherapy anticipated plasma carcinoembryonic antigen progression 1–2 months later and was associated with poor survival. Ten fractionated urines were collected over 2-days in 29 patients. The median value of the rhythm-adjusted mean of urinary nucleoside excretion varied from 64.3 for pseudouridine down to 0.61 for cytidine. The rhythm amplitudes relative to the 24-h mean of 6 nucleoside excretions were associated with rest duration, supporting a tight link between nucleosides turnover and the rest-activity rhythm. Moreover, the amplitude of the 1-methylguanosine rhythm was correlated with the rest-activity dichotomy index, a significant predictor of survival outcome in prior studies. In conclusion, urinary excretion dynamics of modified nucleosides appeared useful for the characterization of the circadian control of cellular proliferation and for tracking early responses to treatments in colorectal cancer patients.

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

Sugar-modified nucleosides have gained considerable attention in the scientific community, either for use as molecular probes or as therapeutic agents. When the methylene group of the ribose ring is replaced with a sulfur atom at the 3’-position, these compounds have proved to be structurally potent nucleoside analogues, and the best example is BCH-189. The majority of methods traditionally involves the chemical modification of nucleoside structures. It requires the creation of artificial sugars, which is accompanied by coupling nucleobases via N-glycosylation. However, over the last three decades, efforts were made for the synthesis of 1,3-oxathiolane nucleosides by selective N-glycosylation of carbohydrate precursors at C-1, and this approach has emerged as a strong alternative that allows simple modification. This review aims to provide a comprehensive overview on the reported methods in the literature to access 1,3-oxathiolane nucleosides. The first focus of this review is the construction of the 1,3-oxathiolane ring from different starting materials. The second focus involves the coupling of the 1,3-oxathiolane ring with different nucleobases in a way that only one isomer is produced in a stereoselective manner via N-glycosylation. An emphasis has been placed on the C–N-glycosidic bond constructed during the formation of the nucleoside analogue. The third focus is on the separation of enantiomers of 1,3-oxathiolane nucleosides via resolution methods. The chemical as well as enzymatic procedures are reviewed and segregated in this review for effective synthesis of 1,3-oxathiolane nucleoside analogues.

Biosynthesis and Degradation of Sulfur Modifications in tRNAs

Various sulfur-containing biomolecules include iron–sulfur clusters that act as cofactors for enzymes, sulfur-containing vitamins such as thiamin, and sulfur-modified nucleosides in RNA, in addition to methionine and cysteine in proteins. Sulfur-containing nucleosides are post-transcriptionally introduced into tRNA molecules, where they ensure precise codon recognition or stabilization of tRNA structure, thereby maintaining cellular proteome integrity. Modulating sulfur modification controls the translation efficiency of specific groups of genes, allowing organisms to adapt to specific environments. The biosynthesis of tRNA sulfur nucleosides involves elaborate ‘sulfur trafficking systems’ within cellular sulfur metabolism and ‘modification enzymes’ that incorporate sulfur atoms into tRNA. This review provides an up-to-date overview of advances in our knowledge of the mechanisms involved. It covers the functions, biosynthesis, and biodegradation of sulfur-containing nucleosides as well as the reaction mechanisms of biosynthetic enzymes catalyzed by the iron–sulfur clusters, and identification of enzymes involved in the de-modification of sulfur atoms of RNA. The mechanistic similarity of these opposite reactions is discussed. Mutations in genes related to these pathways can cause human diseases (e.g., cancer, diabetes, and mitochondrial diseases), emphasizing the importance of these pathways.

Effect of emoxipine on cytotoxicity of peripheral blood mononuclears under cultivation with cytarabine and cyclocytidine

Taking into account the special role of oxidative stress that increases during cancer chemotherapy, the effect of the antioxidant emoxipine on peripheral blood mononuclears was studied under conditions that simulate the cytotoxic effects of antimetabolites of a number of modified cytidine nucleosides in relation to the tumor cell line K562. Lymphoid cells were also a source for subsequent modelling of the immune response to the cancer. It was found that neither the modified nucleosides themselves nor their combination with emoxipine caused changes in IL-2-stimulated cytotoxicity of lymphoid cells in relation to K562 tumor cell line. A study of the expression of the CD107a marker showed a significant stimulating effect of 1 µmol/L of citarabine on the activation of subpopulations of T-lymphocytes (CD3+ ) and cytotoxic T-lymphocytes (CD3+ CD8+ ).

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m6A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m6A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m6A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets.

Long Non-Coding RNA Epigenetics

Long noncoding RNAs exceeding a length of 200 nucleotides play an important role in ensuring cell functions and proper organism development by interacting with cellular compounds such as miRNA, mRNA, DNA and proteins. However, there is an additional level of lncRNA regulation, called lncRNA epigenetics, in gene expression control. In this review, we describe the most common modified nucleosides found in lncRNA, 6-methyladenosine, 5-methylcytidine, pseudouridine and inosine. The biosynthetic pathways of these nucleosides modified by the writer, eraser and reader enzymes are important to understanding these processes. The characteristics of the individual methylases, pseudouridine synthases and adenine–inosine editing enzymes and the methods of lncRNA epigenetics for the detection of modified nucleosides, as well as the advantages and disadvantages of these methods, are discussed in detail. The final sections are devoted to the role of modifications in the most abundant lncRNAs and their functions in pathogenic processes.