Pyrimidine C-nucleosides Research Articles

Synthesis and Anti-Influenza Activity of Pyridine, Pyridazine, and Pyrimidine C-Nucleosides as Favipiravir (T-705) Analogues.

Influenza viruses are responsible for seasonal epidemics and occasional pandemics which cause significant morbidity and mortality. Despite available vaccines, only partial protection is achieved. Currently, there are two classes of widely approved anti-influenza drugs: M2 ion channel blockers and neuraminidase inhibitors. However, the worldwide spread of drug-resistant influenza strains poses an urgent need for novel antiviral drugs, particularly with a different mechanism of action. Favipiravir (T-705), a broad-spectrum antiviral agent, has shown potent anti-influenza activity in cell-based assays, and its riboside (2) triphosphate inhibited influenza polymerase. In one of our approaches to treat influenza infection, we designed, prepared, and tested a series of C-nucleoside analogues, which have an analogy to 2 and were expected to act by a similar antiviral mechanism as favipiravir. Compound 3c of this report exhibited potent inhibition of influenza virus replication in MDCK cells, and its triphosphate was a substrate of and demonstrated inhibitory activity against influenza A polymerase. Metabolites of 3c are also presented.

Synthesis and characterization of 2′-C-Me branched C-nucleosides as HCV polymerase inhibitors

A series of 2′-C-methyl branched purine and pyrimidine C-nucleosides were prepared. Their anti-HCV activity and pharmacological properties were profiled, and compared with known 2′-C-Me N-nucleoside counterparts. In particular, 2′-C-Me 4-aza-7,9-dideazaadenosine C-nucleoside (2) was found to have potent and selective anti-HCV activity in vitro as well as a favorable pharmacokinetic profile and in vivo potential for enhanced potency over the corresponding N-nucleoside.

ChemInform Abstract: Synthesis of a Novel Pyrazolo[1,5-c]pyrimidine C-Nucleoside and Conformational Analysis by NMR Spectroscopy.

Abstract Isopropylidenation of [4-methoxycarbonyl-5-(β-D-ribofuranosyl)-1H-pyrazol-3-yl]acetamide (1a) followed by the acidic cleavage of the sugar acetonide afforded 3-methoxycarbonyl-7, 7-dimethyl-2-(β-D-ribofuranosyl)-4H, 7H-pyrazolo[1,5-c] pyrimidine-5(6H)-one (2b), the structure of which was established unequivocally by X-ray structure analysis of the monocrystals. Compounds 1a and 2b have 75% and 70% preference for the N-type puckering between C3′-endo and C3′-endo-C4′-exo forms, and a great preference of 69% and 74% for γ+ rotamers in solution, respectively.

Synthesis of 2′-Fluoro and 2′,4′-Dimethyl Pyrimidine C-Nucleoside Analogues as Potential Anti-HCV Agents

Stereoselective synthesis of novel 2′-fluoro and 2′,4′-dimethyl carbocyclic pyrimidine C-nucleoside analogues using selective fluorination of an epoxide opening reaction is described. The key fluorinated intermediate 7 was prepared from the epoxide intermediate 5 via selective ring opening of the epoxide. Synthesis of isonucleosidic bases through the mesylate 7 and final deprotection provided the target carbocyclic pyrimidine C-nucleoside analogues. The synthesized compounds 15 and 18 were evaluated as inhibitors of the hepatitis C virus (HCV) in the Huh-7 cell line in vitro.

Synthesis and Anti-Hiv Activity of 4′-Modified Cyclopentenyl Pyrimidine C-Nucleosides

Novel syntheses of 4′-modified cyclopentenyl pyrimidine C-nucleosides were performed via C-C bond formation using SN2 alkylation via the key intermediate mesylates 6 and 16, which were prepared from acyclic ketone derivatives. When antiviral evaluation of synthesized compound was performed against various viruses such as HIV-1, HSV-1 and HSV-2, isocytidine analogue 20 showed moderate anti-HIV activity in CEM cell line (EC50 = 13.1 μmol).7

Synthesis and antiviral evaluation of thieno[3,4- d]pyrimidine C-nucleoside analogues of 2′,3′-dideoxy- and 2′,3′-dideoxy-2′,3′-didehydro-adenosine and -inosine

Several thieno[3,4- d]pyrimidine derivatives, including four hitherto unknown 2′,3′-dideoxy- and 2′,3′-dideoxy-2′,3′-didehydro- C-nucleoside analogues of adenosine and inosine have been synthesized. When evaluated in cell culture experiments against human immunodeficiency virus, none of the tested compounds exhibited any significant antiviral effect, while two of them showed some cytotoxicity.

Enantioselective synthesis and antiviral activity of purine and pyrimidine cyclopentenyl C-nucleosides

The enantiomerically pure carbocyclic purine and pyrimidine C-nucleosides 1– 4 were synthesized via the key intermediate, 2,3-(isopropylidenedioxy)-4-(trityloxymethyl)-4-cyclopenten-1-ol ( 5), which was prepared from d-ribose in eight steps. Synthesized compounds were evaluated as potential antiviral agents against HIV, SARSCoV, Punta Toro, West Nile, and Cowpox viruses. However, only 9-deazaneplanocin A ( 1) exhibited moderate anti-HIV activity.

A Review: Synthesis of Aryl C-Glycosides Via the Heck Coupling Reaction

In this article, we focus on the synthesis of aryl C-glycosides via Heck coupling. It is organized based on the type of structures used in the assembly of the C-glycosides (also called C-nucleosides) with the following subsections: pyrimidine C-nucleosides, purine C-nucleosides, and monocyclic, bicyclic, and tetracyclic C-nucleosides. The reagents and conditions used for conducting the Heck coupling reactions are discussed. The subsequent conversion of the Heck products to the corresponding target molecules and the application of the target molecules are also described.

Syntheses of Pyridine C-Nucleosides as Analogues of the Natural Nucleosides dC and dU

The syntheses of four pyrimidine C-nucleosides are described. These derivatives are designed as mimics of dC and dU, and in that respect, each can form two hydrogen bonds with complementary dG or dA residues. The minor groove O2 carbonyl in each derivative is replaced by a fluorine or a methyl group. The key carbon-carbon bond connecting the heterocycle to the carbohydrate is formed using a Heck-type palladium-mediated coupling reaction.

Synthesis of Racemic 2‐Hydroxy‐4‐ and 2‐Hydroxy‐5‐(hydroxymethyl)cyclohexane Pyrimidine C‐Nucleoside Analogues.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Racemic 2-Hydroxy-4- and 2-Hydroxy-5-(hydroxymethyl)cyclohexane Pyrimidine C-Nucleoside Analogues

The oxirane ring opening of 3-[(benzyloxy)methyl]-7-oxabicyclo[4.1.0]heptane with sodium salt of diethyl malonate followed by treatment with TsOH gave (3aR*,6R*,7aS*)-6-[(benzyloxy)methyl]hexahydro-1-benzofuran-2(3H)-one (3a) and (3aR*,5R*,7aS*)-5-[(benzyloxy)methyl]hexahydro-1-benzofuran-2(3H)-one (3b). Lactones 3a and 3b were formylated and then treated with thiourea or guanidine to give, after deprotection, racemic 5-[2-hydroxy-4- and 2-hydroxy-5-(hydroxymethyl)cyclohexyl]-2-thiouracil (5a and 5b) or -isocytosine (12a and 12b). Simple transformations of the 2-thiouracil derivative led to uracil (7a and 7b), 4-thiouracil (9a and 9b), and cytosine derivatives (10a and 10b).

EFFICIENT SYNTHESIS OF FUSED ISOTHIAZOLO C-NUCLEOSIDES. III. SYNTHESIS OF 7-SUBSTITUTED ISOTHIAZOLO[4,5-d]PYRIMIDINE C-NUCLEOSIDES1*

The Divakar-Reese procedure has been successfully applied for transforming 7-oxo-isothiazolo[4,5-d]pyrimidine C-nucleosides (4a,b, 5a,b, 6a) via 1,2,4-triazol-1-yl intermediates (7a,b, 8a,b) into various 7-substituted C-nucle- osides 15a,b, 16a,b, 17a, 18a, 19a,b, 20a,b; their subsequent deprotection provides novel types of unusual C-glycosides 22b, 23a, 24a,b, 25b, 26b. C-Nucleosides, possessing on its heterocyclic base other than naturally occuring oxo- or amino substituents, are important model compounds for biological or medicinal studies [2a], [2b], [2c], [2d], [2e], [2f], [2g], [2h], [2i][3a], [3b], [3c], [3d], [3e], [3f], [3g], [3h]. We want to report on the synthesis of novel 7-substituted isothiazolo = [4,5-d]pyrimidine C-nucleosides. As we could show in previous papers [1], [4], there exists a simple approach to the protected C-glycosides 4–6. *See reference [1].

ChemInform Abstract: Formation and Reactivity of 2,4-Ditriazolyl Pyrimidine C-Nucleoside Derived from Pseudouridine.

Thymine and 2',3',5'-tri-O-acetyl-psi-uridine (1) was converted into the corresponding 2,4-ditriazolyl derivatives 5 and 2, respectively. Of these two substituents, the C4-triazolyl group was found to be quite susceptible to nucleophilic substitution while the other triazolyl is resistant.

Formation and Reactivity of 2,4-Ditriazolyl Pyrimidine C-Nucleoside Derived from Pseudouridine

Thymine and 2′,3′,5′-tri-O-acetyl-Ψ-uridine (1) was converted into the corresponding 2,4-ditriazolyl derivatives 5 and 2, respectively. Of these two substituents, the C4-triazolyl group was found to be quite susceptible to nucleophilic substitution while the other triazolyl is resistant.

Synthesis of a Novel Pyrazolo[1, 5-C]Pyrimidine C-Nucleoside and Conformational Analysis By NMR Spectroscopy

Isopropylidenation of [4-methoxycarbonyl-5-(β-D-ribofuranosyl)-1H-pyrazol-3-yl]acetamide (1a) followed by the acidic cleavage of the sugar acetonide afforded 3-methoxycarbonyl-7, 7-dimethyl-2-(β-D-ribofuranosyl)-4H, 7H-pyrazolo[1,5-c] pyrimidine-5(6H)-one (2b), the structure of which was established unequivocally by X-ray structure analysis of the monocrystals. Compounds 1a and 2b have 75% and 70% preference for the N-type puckering between C3′-endo and C3′-endo-C4′-exo forms, and a great preference of 69% and 74% for γ+ rotamers in solution, respectively.

A new route to the synthesis of pyrazole and pyrimidine C-nucleoside derivatives

A new route to the synthesis of pyrazole and pyrimidine C-nucleosides, which involves as the key step a metal promoted reaction of β-D-ribofuranosyl ketoesters with alkyl cyanoformates is described. 2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl cyanide 1 reacts with α-bromoesters, in the presence of zinc dust, to give β-D-ribofuranosyl-enaminoesters 2 which are hydrolysed with 1N hydrochloric acid to β-ketoesters 3. The reactions of β-ketoesters 3 with alkyl cyanoformates, in the presence of tin(IV) chloride or of catalytic amounts of metal acetylacetonates, afford β-D-ribofuranosyl enaminoketoesters 4. These compounds react with benzylhydrazine and acetamidine to give pyrazole and pyrimidine C-nucleosides ( 6,7).

A new and efficient route to the synthesis of pyrazole and pyrimidine C-nucleoside derivatives

Abstract A new route to the synthesis of pyrazole and pyrimidine C-nucleosides, involving as the key step a metal catalysed reaction of β-D-ribofuranosyl ketoesters with alkyl cyanoformates, is described, 2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl cyanide (1) reacts with α-bromoesters, in the presence of zinc dust, to give β-D-ribofuranosyl-enaminoesters 2 which are easily hydrolised to β-ketoesters 3. The reactions of compounds 3 with alkyl cyanoformates, in the presence of catalytic amounts of [Cu(acac)2], afford C-glycosyl enaminoketosters 4. These compounds react with benzylhydrazine and acetamidine to give pyrazole and pyrimidine C-nucleosides 5 and 6 respectively.

Triplex Formation at Single-Stranded Nucleic Acid Target Sites of Unrestricted Sequence by Two Added Strands of Oligonucleotides: A Proposed Model

By using the standard purine nucleosides, guanosine and adenosine, and the pyrimidine C-nucleosides, pseudoisocytidine and pseudouridine, as complements on a probe strand, it is possible to construct a regular Watson-Crick helix with a single-stranded target sequence having any arrangement of the four naturally-occurring bases found in nucleic acids. The major groove of this helix will have a unique configuration of hydrogen-bonding sites on the probe strand for each of these four base pairs. By using this duplex as a framework, an ensemble of recognition patterns composed of base triads may be constructed. In these patterns, either a homopyrimidine or homopurine third strand binds in the major groove of the duplex formed by the target and probe strands. Ten distinct geometries, or motifs, are shown, each one consisting of four isomorphic base triads built upon recognition of C, G, A, or U(T) residues in the target strand. In order to maintain specific hydrogen bonding and to construct isomorphous triads, the use of several nonstandard bases is proposed. 33 refs., 9 figs., 3 tabs.

Enantio- and diastereoisomers of 2,4-dimethoxy-5-(2,3-dideoxy-5-O-tritylribofuranosyl)pyrimidine. 2',3'-Dideoxy pyrimidine C-nucleosides by palladium-mediated glycal-aglycon coupling

Newly available enantiomeric 2,3-dideoxy glycals, (5S)- and (5R)-4,5-dihydro-5-[(triphenylmethoxy)methyl]furans and 2,4-dimethoxy-5-iodopyrimidine undergo palladium-mediated coupling by two different, complementary procedures to form enantiomeric pairs of (2',3'-dideoxy-2',3'-didehydrofuranosyl)- and (2',4'-dideoxy-3',4'-didehydrofuranosyl)pyrimidine C-nucleosides. Stereoselective reductions of the carbohydrate unsaturations produce all four enantio- and diastereoisomers of 2,4-dimethoxy-5-(2,3-dideoxy-5-O-tritylribofuranosyl)pyrimidine

C-glycosylation of substituted heterocycles under Friedel-Crafts conditions (I): a two-step synthesis of the thieno[3,4- [formula omitted]]pyrimidine c-nucleoside analog of inosine

Direct stannic chloride catalyzed C-glycosylation of N-formyl-4-amino-3-carboalkoxy thiophenes with 1- O -acetyl-tri- O -benzoyl-β- D -ribofuranose, followed by annelation of a fused pyrimidone ring upon treatment with ammonia, constitutes a short approach to the synthesis of a new C-nucleoside inosine analog.