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Modified C-nucleosides have proven to be enormously successful as chemical probes to understand fundamental biological processes and as small-molecule drugs for cancer and infectious diseases. Historically, the modification of the glycosyl unit has focused on the 2'-, 3'-, and 4'-positions as well as the ribofuranosyl ring oxygen. By contrast, the 1'-position has rarely been studied due to the labile nature of the anomeric position. However, the improved chemical stability of C-nucleosides allows the modification of the 1'-position with substituents not found in conventional N-nucleosides. Herein, we disclose new chemistry for the installation of diverse substituents at the 1'-position of C-nucleosides, including alkyl, alkenyl, difluoromethyl, and fluoromethyl substituents, using the 4-amino-7-(1'-hydroxy-d-ribofuranosyl)pyrrolo[2,1-f][1,2,4]triazine scaffold as a representative purine nucleoside mimetic.

We developed new DNA triplexes that contain four base triads T-A·T, A-ψ·CBr, G-PIC·YO, and C-G·Py+, where CBr, YO, Py, ψ, and PIC are 5-bromocytosine, 5-methyl-4-pyrimidone, 2-aminopyridine, the aglycons of deoxypseudouridine, and deoxypseudoisocytidine, respectively. DNA duplex incorporating T-A, A-ψ, G-PIC, and C-G, and triplex forming oligonucleotide incorporating T, CBr, YO, and Py formed the triplex as evaluated by Tm measurements. The triplex formation was successfully applied to the inhibition of transcription of the DNA duplex incorporating T7-promoter sequence modified by the above modified bases.

Concise synthesis of novel benzoylthiophene C-nucleoside analogues has been achieved by the reaction of various terminal sugar alkynes with substituted benzoyl chlorides and 1,4-dithiane-2,5-diol, and subsequent dilute HCl-promoted dehydration in one pot. The sugar alkynes include pyranosides, furanosides, and acyclic sugar. The benzoyl chloride has various substituents. Twenty-eight examples are given. The desired products are obtained in 70–89% yields, and the mechanism has been clarified by isolation of the intermediate.

Expansion of the triplex DNA forming sequence is required in the genomic targeting fields. Basically, triplex DNA is formed by the interaction between the triplex-forming oligonucleotides and homo-purine region with the target duplex DNA. The presence of the base pair conversion sites hampers stable triplex formation. To overcome this limitation, it is necessary to develop an artificial nucleic acid to recognize the base conversion sites, and the CG and TA base pairs. We describe the synthesis of C-nucleoside analogues and an evaluation of the ability of triplex formation. Consequently, the combined use of the novel C-nucleoside analogues, AY - AY-d(Y-NH2), AY-d(Y-Cl) and IAP-d(Y-Cl), is capable of recognizing duplex DNA including the TA or dUA base pair.

In the last two years, nucleosides analogues, a class of well-established bioactive compounds, have been the subject of renewed interest from the scientific community thanks to their antiviral activity. The COVID-19 global pandemic, indeed, spread light on the antiviral drug Remdesivir, an adenine C-nucleoside analogue. This new attention of the medical community on Remdesivir prompts the medicinal chemists to investigate once again C-nucleosides. One of the essential building blocks to synthetize these compounds is the D-(+)-ribono-1,4-lactone, but some mechanistic aspects linked to the use of different carbohydrate protecting groups remain unclear. Here, we present our investigations on the use of benzylidene as a ribonolactone protecting group useful in the synthesis of C-purine nucleosides analogues. A detailed 1D and 2D NMR structural study of the obtained compounds under different reaction conditions is presented. In addition, a molecular modeling study at the B3LYP/6-31G* level of theory with the SM8 solvation model for CHCl3 and DMSO to support the obtained results is used. This study allows for clarifying mechanistic aspects as the side reactions and structural rearrangements liked to the use of the benzylidene protecting group.

A general synthesis of hetaryl and aryl C-4(5) linked imidazole C-nucleoside analogues has been developed by the reaction of sugar alkynes with het(aryl) iodides, KMnO4/TBAB oxidation and CoFe2O4 NPs catalyzed muti-component coupling of the corresponding diketones, NH4OAc and aromatic aldehydes in one-pot. The sugar alkynes include pyranosides and furanosides with acid sensitive protecting groups. The het(aryl) iodides comprise iodoaromatics, iodoheterocycles, and sterically hindered iodoheteroaromatics.

The synthesis of novel indolizine C-nucleoside analogues has been achieved by the three-component coupling reaction of sugar alkynes, pyridines and α-bromo carbonyl compounds in one pot. The corresponding products are obtained in good to excellent yields. 49 examples have been given. The synthetic method is convenient, practical and efficient. It is suitable for various substrates including structurally diversified sugar alkynes with sensitive groups. The sugar alkynes include pyranosides, furanosides, and acyclic sugars. A plausible mechanism for the formation of indolizine C-nucleoside analogues has been elucidated.

The triplex DNA forming method is an attractive tool as a gene-targeting agent. Using artificial nucleoside analogues based on C-nucleoside, stable and selective triplex DNA can be formed in a specific region of duplex DNA, and its biotechnology applications will greatly expand. In this study, we designed and synthesized novel C-nucleoside analogues based on the pyrimidine skeleton, 3MeAP-d(Y-Cl) and 3MeAP-d(Y-H), capable of recognizing a CG mismatch site that is not recognized by natural nucleosides. After incorporating them into the oligonucleotides, their triplex forming abilities were evaluated by gel-shift assay. Although it was only one sequence, the 3'-GZG-5' sequence, the stability of the CG mismatch site recognition was greatly improved compared with previous nucleoside analogues.

The synthesis of thiophene C-nucleoside analogues bearing sugar residues (mono- and disaccharides) and aromatic residues has been achieved by symmetric dimerization of terminal sugar alkynes or unsymmetric dimerization of terminal sugar alkynes and substituted iodoethynylbenzene followed by sulfur heterocyclization in one pot. Homocoupling of terminal sugar alkynes and subsequent sulfur heterocyclization produce thiophene C-nucleoside analogues bearing disaccharides. Unsymmetric dimerization of terminal sugar alkynes and substituted iodoethynylbenzene followed by sulfur heterocyclization give thiophene C-nucleoside analogues bearing monosaccharide and aromatic residues. This approach is concise, general and mild, and is suitable for structurally diverse pyranosides, furanosides, and acyclic sugars. Thirty-two examples have been given and the corresponding products are obtained in moderate to excellent yields.

New aryl- and heteroaryl-substituted pyridinyl sugar hydrazones and their derivatives, 1,3,4-oxadiazole acyclic C-nucleosides, were synthesized. Novel O-glycoside derivatives of the substituted pyridines were prepared. The antiviral activity against avian influenza H5N1 virus was studied and compounds 5a, 9a, and 14 demonstrated high inhibition activity.

C-nucleosides have intrigued biologists and medicinal chemists since their discovery in 1950's. In that regard, C-nucleosides and their synthetic analogues have resulted in promising leads in drug design. Concurrently, advances in chemical syntheses have contributed to structural diversity and drug discovery efforts. Convergent and modular approaches to synthesis have garnered much attention in this regard. Among them nucleophilic substitution at C1' has seen wide applications providing flexibility in synthesis, good yields, the ability to maneuver stereochemistry as well as to incorporate structural modifications. In this review, we describe recent reports on the modular synthesis of C-nucleosides with a focus on D-ribonolactone and sugar modifications that have resulted in potent lead molecules.

C-Nucleosides constitute a valuable class of compounds in biological and medicinal chemistry studies. We report herein a new and efficient synthesis of both alpha- and beta-C-nucleosides with high anomeric selectivity from N6-Boc protected purine analogues. The synthetic approach features a carefully designed lithiation and silane reduction sequence. The anomeric stereochemistry outcome is dictated by the protecting group of sugar lactones. Computational studies suggest that previously neglected interactions between partially positively-charged silane and the substitutions on a sugar moiety play important roles in the anomeric selectivity of silane-mediated C-nucleoside synthesis.

Condensation of 4-hydrazino-1,3-diphenylpyrazolo[3,4-d]-pyrimidine with the aldohexoses, namely, D-glucose, D-galactose, D-mannose and the aldopentoses, D-arabinose, D-xylose and D-ribose, by heating in an aqueous ethanol in the presence of a catalytic amount of HCl, gave the respective aldehydo-sugar hydrazones. Oxidative cyclisation of such hydrazones by stirring with iron(III) chloride in ethanol at room temperature afforded the expected acyclo C-nucleosides 3-substituted-7,9-diphenylpyrazolo[4,3-e][1,2,4]triazolo[4,3-c]-pyrimidines. The structures of the cyclised sugar hydrazones were confirmed by their elemental analyses and spectral data.

Carbocyclic C-nucleosides are quite rare. Our route enables flexible preparation of three classes of these nucleoside analogs from common precursors-properly substituted cyclopentanones, which can be prepared racemic (in six steps) or optically pure (in ten steps) from inexpensive norbornadiene. The methodology allows flexible manipulation of individual positions around the cyclopentane ring, namely highly diastereoselective installation of carbo- and heterocyclic substituents at position 1', orthogonal functionalization of position 5', and efficient inversion of stereochemistry at position 2'. Newly prepared carbocyclic C-analog of tubercidine, profiled in MCF7 (breast cancer) and HFF1 (human foreskin fibroblasts) cell cultures, is less potent than tubercidine itself, but more selectively toxic toward the tumorigenic cells.

Because of the emergence of new viruses, the need for new antiviral broad-spectrum compounds remains important. In this context, herein the synthesis of C-nucleosides, structurally close to ribavirin, a nucleoside presenting various biological activities and used until now particularly for its broad-spectrum antiviral properties, is reported. The compounds were designed in order to increase their stability and the number of hydrogen bond donor or acceptor in comparison to ribavirin, and to investigate the role of the carboxamide group on the biological activity. The efficient synthesis of 11 C-nucleosides is based on an indium-mediated alkynylglycosylation as the key step, followed by the construction of the triazole heterocycle. Amidation was performed with primary and secondary amines in yields up to 85%. An analogue nucleoside with a triazole without carboxamide group was also prepared in order to compare its activity. Finally, the carboxamide group was moved to the N-1 triazole position to mimic ribavirin.

RNA represents an extremely promising and yet challenging therapeutic target. Here, we report the design of a series of C-nucleosides as original RNA binders. Some of them bind strongly and selectively to A-site prokaryotic ribosomal RNA.

Straightforward and efficient methods for the synthesis of 2-amino-4-fluoropyridine-C-nucleoside (dF P) and the solid-phase synthesis of oligodeoxynucleotides containing dF P using a phosphoramidite are described. The synthesis of dF P is achieved by cross-coupling between a nucleobase (2-amino-4-fluoro-3,5-diiodopyridine) and sugar moieties. Its 3'-O-phosphoramidite is obtained by deiodination, 5'-O-protection, and 3'-O-phosphitilation in three steps. The phosphoramidite unit is compatible for the synthesis of oligonucleotides on solid-phase according to conventional phosphoramidite chemistry. The 2-amino-4-fluoropyridine-C-nucleoside moiety incorporated into the oligodeoxynucleotide reacts with a Cys residue in the catalytic site of DNA cytosine-5-methyltransferase (DNMT). It is apparent that 2-amino-4-fluoropyridine-C-nucleoside would be utilized in DNA-protein crosslink technology. This protocol describes the importance of solid-phase synthesis to obtain novel pyridine-C-nucleoside analogues and its incorporation into oligodeoxynucleotides in a short period of time. © 2019 by John Wiley & Sons, Inc.

Formyl glycals are the versatile synthetic intermediates and can serves as precursor for the synthesis of various C and N-nucleosides. Due to the presence of electron donating and electron withdrawing character on formyl sugars which makes the molecule more susceptible to nucleophilic attack. Utilizing same strategy, we propose the synthesis of diversified C-nucleosides (3-14) by reaction with N,N dinucleophiles. These nucleoside analogs were than tested against viral, bacterial and fungal strains.

A series of homologous C-nucleoside mimics have been synthesized via an efficient and facile synthetic protocol involving the conjugate addition of purine to sugar derived olefinic ester in good yields. The synthesized compounds were evaluated for their antiplasmodial activity in vitro against both the CQ-sensitive and resistant strains of P. falciparum. Interestingly, all the synthesized nucleoside analogs exhibited an IC(50) of

The efficient synthesis of a [2'S] C-nucleoside phosphonate and its corresponding prodrug has been realized. A phosphonomethoxy group was stereoselectively introduced at the anomeric 5'-carbon atom through glycosylation of a benzoyl protected [5'R]-acetoxy-[2'R]-9-deazaadenine. An unexpected epimerization at the 2'-position of the sugar moiety occurred upon removal of the protecting groups, but this was further exploited as a key reaction for improved synthesis of the target compound. ispartof: Organic Letters vol:20 issue:4 pages:1203-1206 ispartof: location:United States status: published

Although DNA has the ability to form almost every desired shape, the usability of DNA nanostructures can be limited due to the lack of functionality. To functionalize nanoscale structures, light-responsive moieties like photoswitchable azobenzenes can be introduced into DNA. Upon UV irradiation, the isomerization of the azobenzene moiety causes destabilization of the neighboring base pairs leading to decreased binding ability. The linker strategy of the azobenzene to the DNA alters the performance of the switching behavior significantly. We hereby report the utilization of four different azobenzene C-nucleosides and compare their features in a nanoarchitecture model with the help of gel-electrophoresis and atomic force microscope-imaging.

In the present paper we have a focus in a study of theoretical characterization of three double headed acyclo-C-nucleosides, which are a recent target of experimental studies. The structural and electronic properties of double headed acyclo-C-nucleosides, 1,4-bis (3-mercapto-1H-1,2,4-triazol-5-yl) butane-1,2,3,4-tetrol, 1,4-bis (4-amino-5-mercapto-4H-1,2,4-triazol-3-yl) butane-1,2,3,4-tetrol and 5,5'-(1,2,3,4-tetrahydroxybutane-1,4-diyl) bis (1,3,4-oxadiazole-2(3H)-thione), have been investigated theoretically by performing semi-empirical molecular orbital, ab initio Hartree-Fock (HF) and Density Functional Theory (DFT) calculations. Geometries of the three molecules are optimized at the level of Austin Model 1 (AM1). The electronic properties and relative energies of the molecules have been calculated by HF and DFT in the ground state.

An efficient procedure was developed to prepare homo-C-nucleosides. The β-allyl C-glycoside of D-ribose was transformed into the thienopyrimidine nucleoside and the benzodiazepine nucleoside of 2-deoxy-D-ribose. For incorporation into oligonucleotides by solid-phase synthesis, both derivatives were transformed into the related 3′-phosphoramidite building blocks. These phosphoramidites were then site-specifically incorporated into DNA oligonucleotides. The modified DNA strands were hybridized with different DNA and RNA strands, and their melting temperatures and circular dichroism spectra were studied. Interestingly, although in the case of DNA–DNA hybrids the nonnatural nucleosides caused a marked decrease in melting temperature, to levels even lower than those for mismatched hybrids, in the case of DNA–RNA hybrids very similar melting temperatures were measured for the nonnatural nucleosides and the unmodified oligonucleotides.

In this study, 18 new 3-benzylquinoxalinyl hydrazones bearing carbohydrate moiety and their corresponding triazoloquinoxalines were synthesized in order to investigate their possible antibacterial and antifungal activities. Some of these compounds such as 4b, 4c, 7b, 7c, and 7d showed promising antibacterial and antifungal activities and were found to have more potent activity compared with that of standard drugs. From structure–activity relationship point of view, increasing the size of the substitutions at position 6 or 7 on the quinoxaline nucleus decreased the antimicrobial activity, while the presence of the hydroxyl groups at C2 (R) and C3 (S) of sugar moieties enhanced the activity. Further, molecular docking studies of the active compounds were performed on different targets belonging to different microorganisms and showed good scoring with further understanding of the various interactions with the active sites of interesting enzymes compared with the co-crystallized ligands.

Pd-catalyzed regio- and stereoselective C-nucleoside synthesis from pyranoid glycals and unactivated N,N-dialkyluracils is described. Depending upon the reaction conditions, either β-hydride or β-heteroatom eliminated C-nucleosides were obtained exclusively. Different glycals with various protecting groups reacted smoothly. Mechanistically, uracil first undergoes electrophilic palladation regioselectively at the C-5 position to generate the active organopalladium species, which then attacks the glycal in a regio- and stereoselective mode to generate C-nucleosides. The method obviates the use of heavy metals such as mercury or preactivation of protected uracils, making it an attractive strategy for C-nucleoside synthesis.

Pyrrolo[2,1- f ][1,2,4]triazine, a unique N N bond-containing heterocycle with a bridgehead nitrogen, was first synthesized in the late 1970s but did not find utility until more than a decade later in the early 1990s when it was incorporated into C-nucleosides as a novel purine-like mimetic. This heterocycle remained at the fringes of medicinal chemistry until a confluence of events spurred by the explosion of the kinase inhibitor field in the early 2000s and the pressing need for novel, druggable scaffolds to occupy that exciting space led to numerous applications against diverse therapeutic targets. This digest will explore the history of this scaffold and the importance of chemistry in propelling drug discovery. The varied uses of this scaffold will be detailed as it progressed from C-nucleosides, to kinase inhibitors, to recognition as a “privileged” template, and finally reemergence in the C-nucleoside field.

International audience; An efficient synthetic pathway leading to two carbonated analogues of ribavirin is described. The key-steps in the synthesis of these ribosyltriazoles bearing a quaternary carbon atom in the 2'-position are an indium-mediated alkynylation and a 1,3-dipolar cyclization.

New [(Indolyl)pyrazolyl]-1,3,4-oxadiazole compounds and their derived thioglycosides as well as the corresponding sugar hydrazones were synthesized. The acyclo C-nucleoside analogs of the oxadiazoline base system were also prepared by reaction of acid hydrazides with aldehydo sugars followed by one pot process encompassing acetylation and cyclization of the synthesized hydrazones. The anticancer activity of the newly synthesized compounds was studied against colorectal carcinoma (HCT116), breast adenocarcinoma (MCF7) and prostate cancer (PC3) human tumor cell lines and a number of compounds showed moderate to high activities.

The preparation of two C-5′-nor-3-deazaaristeromycin dia­stereomeric analogues possessing a bridgehead nitrogen is described from (3aR,4R,6S,6aS)-2,2-dimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol that served as the cyclopentyl unit of the target carbocyclic nucleosides and as the scaffold upon which the compounds were built. The process evolved via a de novo approach for constructing the requisite fused imidazo unit between the aforementioned cyclopentyl ring and a readily available 2,3-dichloropyrazine. The syntheses were accomplished in 11 and 8 steps depending on the diastereomer sought.

The synthesis of substituted mono- and diindole C-nucleoside analogues has been achieved in good to excellent yields by sequential Sonogashira coupling/NaAuCl4-catalyzed heteroannulation reactions of substituted 2-iodoanilines with various sugar terminal alkynes in one pot. The method is general, mild, and efficient and suitable for a wide range of sugar substrates, and 42 examples are given. The amino group of the substituted 2-iodoanilines is unprotected. The sugar terminal alkynes include furanosides, pyranosides, and acyclic glycosides with free hydroxyl groups, sensitive functional subtituents, and various protecting groups having different steric hindrance.

To discover novel nucleosides as potential antiviral agents, 1′,2′-cyclopentyl nucleosides were designed as hybrids of sofosbuvir and GS - 6620 . An asymmetric aldol condensation reaction was used as the key transformation to prepare the versatile 1′,2′-cyclopentyl ribose 6 , which is useful to explore diverse bases at 1′ and its utility was demonstrated via the syntheses of nucleosides 9 and 11 . The 2′-β-methyl-1′,2′-cyclopentyl ribonucleoside scaffold was exemplified via a C-nucleoside which was prepared using a RCM reaction as the key step leading to novel nucleoside 35 .

Nucleoside analogues have long been recognized as prospects for the discovery of direct acting antivirals (DAAs) to treat hepatitis C virus because they have generally exhibited cross-genotype activity and a high barrier to resistance. C-Nucleosides have the potential for improved metabolism and pharmacokinetic properties over their N-nucleoside counterparts due to the presence of a strong carbon-carbon glycosidic bond and a non-natural heterocyclic base. Three 2'CMe-C-adenosine analogues and two 2'CMe-guanosine analogues were synthesized and evaluated for their anti-HCV efficacy. The nucleotide triphosphates of four of these analogues were found to inhibit the NS5B polymerase, and adenosine analogue 1 was discovered to have excellent pharmacokinetic properties demonstrating the potential of this drug class.

The construction of a novel series of enantiopure tetrahydrofuranyl 1,2,3-triazolyl C-nucleoside analogues utilizing click reaction of sugar derived tetrahydrofuranyl alkynes with various ‘in house’ synthesized sugar derived tetrahydrofuranyl azides and an adamantyl azide is described. The biological significance of the synthesized C-nucleosides was highlighted by evaluating them in vitro for anti-bacterial and anti-fungal activity, wherein a number of compounds were found to show excellent anti-bacterial activity and moderate anti-fungal activity.

Simple chiral precursors for the preparation of methylene-expanded C-nucleosides were developed, using as key steps pyrolysis of cellulose to levoglucosenone followed by hydrogenation and introduction of vinyl and ethynyl fragments to the 2-position.

The synthesis of 1-deazacytidine, the C-nucleoside analogue of cytidine, is described. It involves coupling of a protected 2-amino-5-bromopyridine with perbenzylated ribonolactone and transformation of the pyridine ring into the desired substituted pyridone. This synthesis completes the family of C-nucleosidic analogues of natural nucleosides. © 2002 Elsevier Science Ltd. All rights reserved.

A facile and general procedure for the preparation of alkynyl C-nucleosides with varied fluorophores is presented. Sonogashira coupling was used as a key reaction to conjugate the dyes to an easily accessible ethynyl functionalized deoxyribose derivative. The new C-nucleosides were used for the preparation of DNA-based polyfluorophores.

A two-step process for the transformation of readily available carbohydrate derivatives into acyclic C-nucleosides is described. The carbohydrate undergoes a scission process that is followed by the addition of aryl ketone derivatives, allowing the introduction of a variety of aryl rings. The resulting acyclic C-nucleosides are transformed into 2-deoxy cyclic pyranosides in good yield and excellent stereoselectivity., This work was supported by the Research Program CTQ2009-07109 of the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministerio de Ciencia e Innovación (currently Economı́a y Competitividad), Spain. We also acknowledge financial support from FEDER funds (European Funds for Regional Development).

In 1-deoxy-xylofuranose derivatives possessing a good leaving group at 2-C, participation of allyloxy and propargyloxy substituents at 5-C results in loss of the 2-C substituent and attack of various nucleophiles at 5-C of the oxonium intermediate. Such participation of a benzyloxy or crotyloxy group leads to dioxabicyclo[2.2.1]heptane rings.

2-Deoxy-C-nucleosides are a subcategory of C-nucleosides that has not been explored extensively, largely because the synthesis is less facile. Flexible synthetic procedures giving access to 2-deoxy-C-nucleosides are therefore of interest. To exemplify the versatility and highlight the limitations of a synthetic route recently developed to that effect, the first synthesis of 2-deoxy benzamide riboside is reported. Biological properties of this novel C-nucleoside are also discussed.

The C-glycosyl alkynecarboxylic acid orthoamides 22 and 23 are proposed as versatile precursors for the synthesis of new types of C-nucleoside analogs. The new synthetic strategy includes alkynylation of protected aldoses 13 or ketoses by Grignard ethynylation or Barbier propargylation, O-protection of the resulting alkynols 14-16, and nucleophilic addition of the metalated protected terminal alkynes 20 and 21 to peralkylguanidinium salt 2 to afford the corresponding alkynecarboxylic acid orthoamides 22 and 23, which in reactions with mono or bis-nucleophiles could serve as building blocks for the construction of a wide variety of C-nucleoside-like binary conjugates. All the steps are demonstrated on 2,4,3,5-bis(4-methoxybenzylidene)-protected L-xylose 11 as a model compound. The synthesis of a representative series of C-glycosidic conjugates of highly substituted “push-pull” 1,3-butadienes 32-35, pyrimidines 24-31, and 2-pyridones 36-39 is included. The stereochemistry of all described compounds is established by 2D-NMR techniques. A general character of the proposed synthetic strategy, when applied to different appropriately protected sugar derivatives, is suggested, and a biomedical applicability of the described type of conjugates is expected.

Synthesis of 4′-C-modified nucleosides and their derivatives, as well as the structure-activity relationship toward hepatitis C virus were discussed.