Unprotected Nucleosides Research Articles

The P(III)-Amidite Based Synthesis of Stable Isotope Labeled mRNA-Cap-Structures Enables their Sensitive Quantitation from Brain Tissue.

The 5' cap structure is crucial to mRNA function, with its diverse methylation patterns depending on the cellular state. Sensitive analytical methods are sought after to quantify this cap variety also referred to as cap epitranscriptome. To address a bottleneck for accurate and precise quantitation, we report a facile and fast access to high-quality synthetic standards via a new route, involving P(III)-amidite chemistry. A range of cap nucleotides and their stable heavy isotopic labeled analogues were derived from nucleoside diphosphates, which themselves were directly prepared in a one-step reaction sequence starting from unprotected nucleosides using a triphosphorylating reagent in combination with ethylenediamine. Considering a wider scope, the route also enables direct access to magic spot nucleotides and diphosphates of isoprenyl-alcohols. Stable-isotope labeled cap nucleotides derived from this route paved the way for the development of a highly sensitive LC-MS/MS method, applied to the characterization of mouse brain cap epitranscriptomes, which turned out to be very different from those of cultured cell lines of widespread use in the life sciences.

Anionic Olefin Metathesis Catalysts Enable Modification of Unprotected Biomolecules in Water.

Stability problems have limited the uptake of cationic olefin metathesis catalysts in chemical biology. Described herein are anionic catalysts that improve water-solubility, robustness, and compatibility with biomolecules such as DNA. A sulfonate tag is installed on the cyclic (alkyl)(amino) carbene (CAAC) ligand platform, chosen for resistance to degradation by nucleophiles, base, water, and β-elimination. Hoveyda-Grubbs catalysts bearing the sulfonated CAAC ligands deliver record productivity in metathesis of unprotected carbohydrates and nucleosides at neutral pH. Decomposed catalyst has negligible impact on metathesis selectivity, whereas N-heterocyclic carbene (NHC) catalysts degrade rapidly in water and cause extensive C=C migration.

Na2[Pd(saccharinate)4]: A new phosphine-free water-soluble catalyst with singular structure for modification of ribose nucleosides at room temperature

The easy synthesis of the anionic palladium catalyst containing saccharinate as only ligand Na2[Pd(saccharinate)4] (I), starting from either Na2[PdCl4] or Pd(AcO)2, is reported here, together with its complete characterization. It includes high resolution powder X-ray diffraction pattern obtained on a synchrotron source, subsequent elucidation of the crystal structure, and structural refinement using the Rietveld method. The structure consists of linear chains that are linked by non-covalent interactions, and results in a porous structure with channels. This air and light water-soluble complex has shown an outstanding performance for room temperature Pd-catalyzed Suzuki functionalization of the purine base in unprotected nucleosides, improving the best results reported to date.

Synthesis, Base Pairing Properties, and Biological Activity Studies of Platinum(II) Complexes Based on Uracil Nucleosides.

The synthesis and base pairing properties of platinum complexes based on uridine and deoxyuridine nucleosides and preliminary studies of their antiproliferative activity are described. Platinum(II) uridine and deoxyuridine complexes were synthesized by C-I oxidative addition to Pt(0)(PPh3)4. First, the synthesis was performed with protected nucleosides to generate complexes 1 and 2, which were deprotected under basic conditions, affording complexes 3 and 4 in good yields. The synthesis with the unprotected nucleosides was also performed and provided complexes 3 and 4 effectively. Base pairing interactions were measured for complex 1, either for self-base pairing or for the Watson-Crick base pair. Complex 1 undergoes self-base pairing in CDCl3, and this aggregation was found not to be dependent on metalation. Contrastingly, for the Watson-Crick base pair with adenine, base pairing was also observed, but metalation was found to affect hydrogen bonding considerably. Complexes 3 and 4 and the corresponding ligand precursors were evaluated for their antiproliferative activity against human glioblastoma cell line U-251. The compounds showed IC50 values of 3.30 (3) and 1.84 (4) μM but are also toxic for nontumorous cell lines.

NHC Catalysis Permits Regioselective C3–OH or C5–OH Acylation of Unprotected Nucleosides

NHC Catalysis Permits Regioselective C3–OH or C5–OH Acylation of Unprotected Nucleosides

Water-Soluble Pd-Imidate Complexes as Versatile Catalysts for the Modification of Unprotected Halonucleosides.

Modification of unprotected nucleosides has been attracting continuous interest, since these building blocks themselves and their phosphate-upgraded corresponding nucleotides have shown a plethora of uses in fields like biochemistry or pharmacy. Pd-catalyzed cross-coupling reactions, conducted in water or its mixtures with polar organic solvents, have frequently been the researchers' choice for the functionalization of the purine/pyrimidine base of the unprotected nucleosides. In this scenario, the availability of hydrophilic ligands and its water-soluble palladium complexes has markedly set the pace of the advances. The approach of our group to the synthesis of such complexes, Pd-imidates specifically, has faced critical stages, namely the jump to synthesize water soluble complexes from our experience working in conventional solvents, the preparation of phosphine free complexes and the overall goal of getting catalytic systems able to work close to room temperature. The continuous feedback with Kapdi's group, experienced in the chemistry of nucleosides, has produced over the last decade the interesting results in both fields presented here.

Synthesis of C6-Substituted Purine Nucleoside Analogues via Late-Stage Photoredox/Nickel Dual Catalytic Cross-Coupling.

Nucleoside analogues have been and continue to be extremely important compounds in drug discovery. Despite the significant effort dedicated to their synthesis, medicinal chemistry campaigns around these structures are often hampered by synthetic challenges. We describe a strategy for the functionalization of purine nucleosides via photoredox and nickel-catalyzed sp2-sp3 cross-coupling. The conditions described herein allow for coupling of unprotected nucleosides with readily available alkyl bromides, providing opportunities for their application to parallel medicinal chemistry.

Operationally Simple Regioselective 5′-Phosphorylation of Unprotected 5-Ethynyl-2′-deoxyuridine Analogues

Here, we present the development of a straightforward methodology to regioselectively phosphorylate the 5′-OH group of unprotected nucleosides. We employ cyclosaligenyl phosphoramidite reagents together with pyridinium trifluoroacetate as activator, followed by in situ oxidation to prepare a panel of novel nucleoside-based chemical probes, ProLabel compounds 4–15. Alternative procedures for this transformation are available, but are limited in number and scope. Furthermore, the benefits of the new methodology include milder reaction conditions, wider solvent applicability, and, by avoiding sensitive reagents, a more straightforward handling of reagents, reactions, and workup processes. The panel of novel cyclosaligenyl phosphotriester uridine ProLabels have variable 2′ substituents (H, F, Cl, Br, I) as well as four different cyclosaligenyl groups that would span a range of half-lives for in vitro applications.

Regioselective O-Glycosylation of Nucleosides via the Temporary 2',3'-Diol Protection by a Boronic Ester for the Synthesis of Disaccharide Nucleosides.

Disaccharide nucleosides, which consist of disaccharide and nucleobase moieties, have been known as a valuable group of natural products having multifarious bioactivities. Although chemical O-glycosylation is a commonly beneficial strategy to synthesize disaccharide nucleosides, the preparation of substrates such as glycosyl donors and acceptors requirestedious protectinggroup manipulations and a purification at each synthetic step. Meanwhile, several research groups have reported that boronic and borinic esters serve as a protecting or activating group of carbohydrate derivatives to achieve the regio- and/or stereoselective acylation, alkylation, silylation, and glycosylation. In this article, we demonstrate the procedure for the regioselective O-glycosylation of unprotected ribonucleosides utilizing boronic acid. The esterification of 2',3'-diol of ribonucleosides with boronic acid makes the temporary protection of diol, and, following O-glycosylation with a glycosyl donor in the presence of p-toluenesulfenyl chloride and silver triflate, permits the regioselective reaction of the 5'-hydroxyl group to afford the disaccharide nucleosides. This method could be applied to various nucleosides, such as guanosine, adenosine, cytidine, uridine, 5-metyluridine, and 5-fluorouridine. This article and the accompanying video representuseful (visual) information for the O-glycosylation of unprotected nucleosides and their analogs for the synthesis of not only disaccharide nucleosides, but also a variety of biologically relevant derivatives.

Effect of temperature modulations on TEMPO-mediated regioselective oxidation of unprotected carbohydrates and nucleosides

Regioselective oxidation of unprotected and partially protected oligosaccharides is a much sought-after goal. Herein, we report a notable improvement in the efficiency of TEMPO-catalyzed oxidation by modulating the temperature of the reaction. Mono-, di-, and tri-saccharides are oxidized regioselectively in yields of 75 to 92%. The present method is simple to implement and is also applicable for selective oxidations of other mono- and poly-hydroxy compounds including unprotected and partially protected nucleosides.

One flask synthesis of 2′,3′-cyclic nucleoside monophosphates from unprotected nucleosides using activated cyclic trimetaphosphate

The 2′,3′-cyclic nucleoside monophosphates (2′,3′-cNMPs) of adenosine, guanosine, cytidine, and uridine were prepared in good yield in a one pot reaction from unprotected ribonucleosides and activated trimetaphosphate in the presence of N-methylimidazole, 4-nitroimidazole and MgCl2.

ChemInform Abstract: Recent Trends in Nucleotide Synthesis

AbstractReview: 270 refs.

Recent Trends in Nucleotide Synthesis

Focusing on the recent literature (since 2000), this review outlines the main synthetic approaches for the preparation of 5'-mono-, 5'-di-, and 5'-triphosphorylated nucleosides, also known as nucleotides, as well as several derivatives, namely, cyclic nucleotides and dinucleotides, dinucleoside 5',5'-polyphosphates, sugar nucleotides, and nucleolipids. Endogenous nucleotides and their analogues can be obtained enzymatically, which is often restricted to natural substrates, or chemically. In chemical synthesis, protected or unprotected nucleosides can be used as the starting material, depending on the nature of the reagents selected from P(III) or P(V) species. Both solution-phase and solid-support syntheses have been developed and are reported here. Although a considerable amount of research has been conducted in this field, further work is required because chemists are still faced with the challenge of developing a universal methodology that is compatible with a large variety of nucleoside analogues.

Simple and Clean Photoinduced Aromatic Trifluoromethylation Reaction.

We describe a simple, metal- and oxidant-free photochemical strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes under either ultraviolet or visible light irradiation. We demonstrated that photoexcited aliphatic ketones, such as acetone and diacetyl, can be used as promising low-cost radical initiators to generate CF3 radicals from sodium triflinate efficiently. The broad utility of this strategy and its benefit to medicinal chemistry are demonstrated by the direct trifluoromethylation of unprotected bidentate chelating ligand, xanthine alkaloids, nucleosides, and related antiviral drug molecules.

ChemInform Abstract: Palladium‐catalyzed Modification of Unprotected Nucleosides, Nucleotides, and Oligonucleotides

AbstractReview: 124 refs.

Palladium-catalyzed modification of unprotected nucleosides, nucleotides, and oligonucleotides.

Synthetic modification of nucleoside structures provides access to molecules of interest as pharmaceuticals, biochemical probes, and models to study diseases. Covalent modification of the purine and pyrimidine bases is an important strategy for the synthesis of these adducts. Palladium-catalyzed cross-coupling is a powerful method to attach groups to the base heterocycles through the formation of new carbon-carbon and carbon-heteroatom bonds. In this review, approaches to palladium-catalyzed modification of unprotected nucleosides, nucleotides, and oligonucleotides are reviewed. Polar reaction media, such as water or polar aprotic solvents, allow reactions to be performed directly on the hydrophilic nucleosides and nucleotides without the need to use protecting groups. Homogeneous aqueous-phase coupling reactions catalyzed by palladium complexes of water-soluble ligands provide a general approach to the synthesis of modified nucleosides, nucleotides, and oligonucleotides.

Heck and Sonogashira couplings in aqueous media – application to unprotected nucleosides and nucleotides

Amongst all synthetic nucleosides having high potential biological activities, C5-modified pyrimidines and C7-deaza or C8-modified purines have been particularly studied. These main chemical modifications have been developed using palladium cross-coupling reactions. This review focus on both Heck and Sonogashira cross-coupling of nucleosides using different aspects of the twelve principles of green chemistry: use of aqueous medium and no protection/deprotection steps.

Aqueous microwave-assisted cross-coupling reactions applied to unprotected nucleosides.

Metal catalyzed cross-coupling reactions have been the preferred tools to access to modified nucleosides (on the C5-position of pyrimidines and on the C7- or C8-positions of purines). Our objective is to focus this mini-review on the Suzuki-Miyaura and on the Heck cross-couplings of nucleosides using microwave irradiations which is an alternative technology compatible with green chemistry and sustainable development

ChemInform Abstract: Palladium‐Catalyzed Suzuki Reaction in Aqueous Solvents Applied to Unprotected Nucleosides and Nucleotides

AbstractReview: [56 refs.

Synthesis of Novel Peptidyl Adenosine Antibiotic Analogs

A small library of peptidyl adenosine antibiotic analogs was synthesized, under the Pilot Scale Library Program of the NIH Roadmap initiative, from 2′,3′-O-isoproylideneadenosine-5′-carboxylic acid 2 in excellent yield. The coupling of the amino terminus of L-2-aminophenylbutyric methyl ester to a free 5′-carboxylic acid moiety of 2 followed by sodium hydroxide treatment led to carboxylic acid analog 4. Hydrolysis of this latter gave unprotected nucleoside analog 5. Intermediate 4 served as the precursor for the preparation of novel peptidyl adenosine analogs 6–18 in good yields and high purity through peptide coupling reactions to diverse amine derivatives. No marked anticancer and antimalaria activity was noted on preliminary cellular testing; however these analogs should be useful candidates for other types of biological activity.