Heterocycles constitute the largest and the most diverse family of organic compounds Among them, aromatic heterocycles represent structural motifs found in a great number of biologically active natural and synthetic compounds, drugs, and agrochemicals Moreover, aromatic heterocycles are widely used for synthesis of dyes and polymeric materials of high value 1 There are numerous reports on employment of aromatic heterocycles as intermediates in organic synthesis 2

Although, a variety of highly efficient methodologies for synthesis of aromatic heterocycles and their derivatives have been reported in the past, the development of novel methodologies is in cuntinious demand Particlularly, development of new synthetic approaches toward heterocycles, aiming at achieving greater levels of molecular complexity and better functional group compatibilities in a convergent and atom economical fashions from readily accessible starting materials and under mild reaction conditions, is one of a major research endeavor in modern synthetic organic chemistry Transition metal-catalyzed transformations, which often help to meet the above criteria, are among the most attractive synthetic tools

Several excellent reviews dealing with transition metal-catalyzed synthesis of heterocyclic compounds have been published in literature during recent years Many of them highlighted the use of a particular transition metal, such as gold,3 silver,4 palladium,5 copper,6 cobalt,7 ruthenium,8 iron,9 mercury,10 rare-earth metals,11 and others Another array of reviews described the use of a specific kind of transformation, for instance, intramolecular nucleophilic attack of heteroatom at multiple C–C bonds,12 Sonogashira reaction,13 cycloaddition reactions,14 cycloisomerization reactions,15 C–H bond activation processes,16 metathesis reactions,17 etc Reviews devoted to an application of a particular type of starting materials have also been published Thus, for example, applications of isocyanides,18 diazocompounds,19 or azides20 have been discussed In addition, a significant attention was given to transition metal-catalyzed multicomponent syntheses of heterocycles21 Finally, syntheses of heterocycles featuring formation of intermediates, such as nitrenes,22 vinylidenes,23 carbenes, and carbenoids24 have also been reviewed

The main focus of the present review is a transition metal-catalyzed synthesis of aromatic monocyclic heterocycles The organization of the review is rather classical and is based on a heterocycle, categorized in the following order: (a) ring size of heterocycle, (b) number of heteroatoms, (c) type of heterocycle, and (d) a class of transformation involved A brief mechanistic discussion is given to provide information about a possible reaction pathway when necessary The review mostly discusses recent literature, starting from 200425 until the end of 2011, however, some earlier parent transformations are discussed when needed

Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles

Synthetic photoswitches have been known for many years, but their usefulness in biology, pharmacology, and medicine has only recently been systematically explored. Over the past decade photopharmacology has grown into a vibrant field. As the photophysical, pharmacodynamic, and pharmacokinetic properties of photoswitches, such as azobenzenes, have become established, they have been applied to a wide range of biological targets. These include transmembrane proteins (ion channels, transporters, G protein-coupled receptors, receptor-linked enzymes), soluble proteins (kinases, proteases, factors involved in epigenetic regulation), lipid membranes, and nucleic acids. In this review, we provide an overview of photopharmacology using synthetic switches that have been applied in vivo, i.e., in living cells and organisms. We discuss the scope and limitations of this approach to study biological function and the challenges it faces in translational medicine. The relationships between synthetic photoswitches, natural...

In Vivo Photopharmacology.

Post-transcriptional ribonucleotide modification is a phenomenon best studied in tRNA, where it occurs most frequently and in great chemical diversity. This paper reviews the intrinsic network of modifications in the structural core of the tRNA, which governs structural flexibility and rigidity to fine-tune the molecule to peak performance and to regulate its steady-state level. Structural effects of RNA modifications range from nanometer-scale rearrangements to subtle restrictions of conformational space on the angstrom scale. Structural stabilization resulting from nucleotide modification results in increased thermal stability and translates into protection against unspecific degradation by bases and nucleases. Several mechanisms of specific degradation of hypomodified tRNA, which were only recently discovered, provide a link between structural and metabolic stability.

tRNA stabilization by modified nucleotides.

Alternative foldings are an inherent property of RNA and a ubiquitous problem in scientific investigations. To a living organism, alternative foldings can be a blessing or a problem, and so nature has found both, ways to harness this property and ways to avoid the drawbacks. A simple and effective method employed by nature to avoid unwanted folding is the modulation of conformation space through post-transcriptional base modification. Modified nucleotides occur in almost all classes of natural RNAs in great chemical diversity. There are about 100 different base modifications known, which may perform a plethora of functions. The presumably most ancient and simple nucleotide modifications, such as methylations and uridine isomerization, are able to perform structural tasks on the most basic level, namely by blocking or reinforcing single base-pairs or even single hydrogen bonds in RNA. In this paper, functional, genomic and structural evidence on cases of folding space alteration by post-transcriptional modifications in native RNA are reviewed.

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Post-transcriptional nucleotide modification and alternative folding of RNA.

While natural and synthetic N-nucleosides are vulnerable to enzymatic and acid-catalyzed hydrolysis of the nucleosidic bond, their C-analogues are much more stable. Several C-nucleosides are naturally occurring compounds, e.g., pseudouridine (isolated from the yeast t-RNA) and showdomycin (an antibiotic). Development of novel synthetic methodologies allowed the preparation of a large variety of synthetic analogues, which found numerous applications in medicinal chemistry and chemical biology. Most important biologically active C-nucleosides are the inhibitors of purine nucleosides phosphorylase or IMP dehydrogenase. A number of artificial aryl-C-nucleosides capable of π-stacking are being vigorously investigated as building blocks in chemical biology. In the past few years, several Artificial Expanded Genetic Information Systems (AEGIS)1 have been successfully developed as prime examples of synthetic biology, a newly emerging interdisciplinary area, with the ultimate goal to design systems where high-level behaviors of the living matter are mimicked by artificial chemical systems.2,3

C-nucleosides: synthetic strategies and biological applications.

The synthesis of 3-methylpseudouridine (m3Ψ) phosphoramidite, 5‘-O-[benzhydryloxybis(trimethylsilyloxy)silyl]-2‘-O-[bis(2-acetoxyethoxy)methyl]-3-methylpseudouridine-3‘-(methyl-N,N-diisopropyl)phosphoramidite, is reported. Selective pivaloyloxymethyl protection of the Ψ N1 followed by methylation at N3 was used to generate the naturally occurring pseudouridine analogue. The m3Ψ phosphoramidite was used in combination with pseudouridine (Ψ) and standard base phosphoramidites to synthesize a 19-nucleotide RNA representing helix 69 of Escherichia coli 23S ribosomal RNA (rRNA) (residues 1906−1924), containing a single m3Ψ at position 1915 and two Ψ's at positions 1911 and 1917. Our synthesis of the fully modified helix 69 RNA demonstrates the ability to make milligram quantities of RNA that can be used for further high-resolution structure studies. Site-selective introduction of the methyl group at the N3 position of pseudouridine at position 1915 causes a slight increase in the thermodynamic stability of the...

Synthesis of helix 69 of Escherichia coli 23S rRNA containing its natural modified nucleosides, m3ψ and ψ

The helix 69 (H69) region of the large subunit (28S) rRNA of Homo sapiens contains five pseudouridine (Psi) residues out of 19 total nucleotides (26%), three of which are universally or highly conserved. In this study, the effects of this abundant modified nucleotide on the structure and stability of H69 were compared with those of uridine. The role of a loop nucleotide substitution from A in bacteria (position 1918 in Escherichia coli 23S rRNA) to G in eukaryotes (position in 3734 in H. sapiens) was also examined. The thermodynamic parameters were obtained through UV melting studies, and differences in the modified and unmodified RNA structures were examined by 1H NMR and circular dichroism spectroscopy. In addition, a [1,3-15N]Psi phosphoramidite was used to generate H69 analogs with site-specific 15N labels. By using this approach, different Psi residues can be clearly distinguished from one another in 1H NMR experiments. The effects of pseudouridine on H. sapiens H69 are consistent with previous studies on tRNA, rRNA, and snRNA models in which the nucleotide offers stabilization of duplex regions through PsiN1H-mediated hydrogen bonds. The overall secondary structure and base-pairing patterns of human H69 are similar to the bacterial RNA, consistent with the idea that ribosome structure and function are highly conserved. Nonetheless, pseudouridine-containing RNAs have subtle differences in their structures and stabilities compared to the corresponding uridine-containing analogs, suggesting possible roles for Psi such as maintaining translation fidelity.

/pdf/effects-of-nucleotide-substitution-and-modification-on-the-mbeu8sw54a.pdf

Effects of nucleotide substitution and modification on the stability and structure of helix 69 from 28S rRNA.

There is considerable attention directed at chemically modifying nucleic acids with robust functional groups in order to alter their properties. Since the breakthrough of copper-assisted azide-alkyne cycloadditions (CuAAC), there have been several reports describing the synthesis and properties of novel triazole-modified nucleic acid derivatives for potential downstream DNA- and RNA-based applications. This review will focus on highlighting representative novel nucleic acid molecular structures that have been synthesized via the “click” azide-alkyne cycloaddition. Many of these derivatives show compatibility for various applications that involve enzymatic transformation, nucleic acid hybridization, molecular tagging and purification, and gene silencing. The details of these applications are discussed. In conclusion, the future of nucleic acid analogues functionalized with triazoles is promising.

https://www.mdpi.com/1420-3049/17/11/12665/pdf

Chemical Architecture and Applications of Nucleic Acid Derivatives Containing 1,2,3-Triazole Functionalities Synthesized via Click Chemistry

The 1H NMR spectra of RNAs representing E. coli23S rRNA helix 69 with [1,3-15N]pseudouridine modification at specific sites reveal unique roles for pseudouridine in stabilizing base-stacking interactions in the hairpin loop region.

Jean-Paul Desaulniers

Papers

Synthesis of helix 69 of Escherichia coli 23S rRNA containing its natural modified nucleosides, m3ψ and ψ

Effects of nucleotide substitution and modification on the stability and structure of helix 69 from 28S rRNA.

Chemical Architecture and Applications of Nucleic Acid Derivatives Containing 1,2,3-Triazole Functionalities Synthesized via Click Chemistry

Pseudouridines in rRNA helix 69 play a role in loop stacking interactions

Synthesis of 15N-enriched pseudouridine derivatives