Carbocyclic Nucleosides Research Articles

Current Strategies on the Enantioselective Synthesis of Modified Nucleosides

AbstractThe isolation of two carbocyclic nucleosides, viz., neplanocin A and aristeromycin, from natural sources, triggered a revolution in the scientific community, leading to the development of more versatile and therapeutically useful compounds. For this purpose, many new methods for the synthesis of the carbocyclic framework of nucleosides have been developed. These efforts resulted in the successful development of many marketable drugs. The inherent benefits associated with carbocyclic nucleosides, such as higher lipophilicity and metabolic stability, resistance against glycosidic hydrolysis and the ability to modify aromatic bases by cellular phosphorylases, make them popular for the development of drugs against cancer and different viruses. Classically, carbocyclic nucleosides of various ring sizes and configurations have been synthesized starting from chiral pool substrates, such as ribose, glucose, etc., but recently, many other new asymmetric versions have been developed. Herein, we present recent developments on the catalytic enantioselective synthesis of nucleoside analogues, including carbocyclic and other varieties. This account provides new insights into the future development of modified nucleosides.1 Introduction2 Cyclic Nucleosides3 Acyclic Nucleosides4 Conclusion

Dual active pyrimidine-based carbocyclic nucleoside derivatives: synthesis, and in silico and in vitro anti-diabetic and anti-microbial studies.

Diabetes mellitus (DM) is a chronic metabolic disorder marked by high blood glucose levels, impairing glucose production in the body. Its prevalence has steadily risen over the past decades, leading to compromised immunity and heightened susceptibility to microbial infections. Immune dysfunction associated with diabetes raises vulnerability, while neuropathy dulls sensation in the extremities, reducing injury awareness. Hence, the development of novel chemical compounds for anti-diabetic and anti-infective treatments is imperative to mitigate adverse effects. In this study, we designed and synthesized pyrimidine-based carbocyclic nucleoside derivatives with C-4 substitution to assess their potential in inhibiting α-glucosidase for managing diabetes mellitus (DM) and microbial infections. Compounds 8b and 10a displayed promising IC50 values against α-glucosidase (43.292 nmol and 48.638 nmol, respectively) and noteworthy docking energies (-9.4 kcal mol-1 and -10.3 kcal mol-1, respectively). Additionally, compounds 10a and 10b exhibited better antimicrobial activity against Bacillus cereus, with the zone of inhibition values of 2.2 ± 0.25 mm and 1.4 ± 0.1 mm at a 100 μl concentration, respectively. Compound 10a also exhibited a modest zone of inhibition of 1.2 ± 0.15 mm against Escherichia coli at 100 μl.

Theoretical Studies of Molecular Structure, Drug Likeness and QSAR Modeling of some Carbocyclic Nucleosides against HIV-1

This paper provides the molecular structure, electronic structure, and QSAR character of 18 carbanucleoside. These antivirals are useful in treating HIV-1 infection. It was determined by molecular mechanics, PM3, QSAR, and ab initio/HF 6-311G(d,p) and DFT/B3LYP 6-311G (d,p) basis sets. These methods were used to determine the structure, electronic properties and energy of studied molecules. The electronic parameters and the biological activity of this antiviral by studying the effect of substitutions of the basic nucleus (9h-purine), which have an effect on the electronic and structural properties of carbanucleoside. The values calculated are HOMO and LUMO, the heat of formation, dipole moments, and Mulliken charges. QSAR properties and Lipinski parameters have been reported and discussed in terms of reporting and analyzing carbanucleoside biological activity. Which indicates that the developed QSAR models are valid and of high quality (R2 = 0.85).

Reversal of Enantioselectivity for the Desymmetrization of meso-1,2-Diols Catalyzed by Pyridine-N-oxides.

The desymmetrization of meso-vic-diols with a reversal of enantioselectivity catalyzed by chiral pyridine-N-oxides with l-proline as a single source of chirality is reported. With chiral 3-substituted ArPNO C2c and 2-substituted 4-(dimethylamino)pyridine-N-oxide C3b as catalysts, a wide range of monoesters were obtained with satisfactory results with a complete and controlled switch in stereoselectivity (up to 97:3 and 1:99 er). Chiral six-membered carbocyclic uracil nucleosides were generated with excellent enantioselectivities after derivatization. A series of control experiments and density functional theory (DFT) calculations supported that the reaction proceeded in a bifunctional activated manner, where the N-oxide groups and N-H proton of the amides were vital for catalytic reactivity and stereocontrol. The DFT calculation also supported the distance-directed switching of enantioselectivity, in which the l-prolinamide moiety moved from the C3 to C2 position on the pyridine ring, resulting in the H-bond interaction between the amide N-H and OH group of meso-vic-diol also shifted from one hydroxyl group to another.

A Stereoselective Synthesis of 4′‐α‐Fluoro‐methyl Carbocyclic Nucleoside Analogs

AbstractThe 4′ position modifications in carbocyclic nucleosides have not been investigated much as potential antiviral agents. Due to the higher ring strain and torsion of the cyclopentyl carbocyclic ring, it is not easy to carry out the modification at the 4′ position. Therefore, there is a need for a procedure that may tackle the synthesis of 4′ position substituted carbocyclic pentyl ring. In this communication, a stereoselective synthesis of 4′‐α‐fluoro‐methyl carbocyclic nucleosides has been reported. A stereoselective synthesis of the 4‐α‐fluoro‐methyl carbocyclic sugar moiety (16) was carried out via carbocyclic ketone 1. The oxidation of the 5‐methyl hydroxy of 9 followed by the aldol condensation gave a diol 11, which via selective protection followed by selective fluorination, yielded a MOM‐protected 4‐α‐fluoro‐methyl carbocyclic ring (16). Compound 16 served as a key intermediate for the synthesis of purines (21&24) and pyrimidine (28&31) nucleosides. The described synthesis may be utilized to construct the various 4′ position modified carbocyclic nucleos(t)ides for an elaborated structure‐activity relationship (SAR) as an antiviral and anticancer agent.

Purine containing carbonucleoside phosphonate analogues as novel chemotype for Plasmodium falciparum Inhibition

The nucleotidase ISN1 is a potential therapeutic target of the purine salvage pathway of the malaria parasite Plasmodium falciparum. We identified PfISN1 ligands by in silico screening of a small library of nucleos(t)ide analogues and by thermal shift assays. Starting from a racemic cyclopentyl carbocyclic phosphonate scaffold, we explored the diversity on the nucleobase moiety and also proposed a convenient synthetic pathway to access the pure enantiomers of our initial hit (compound (±)-2). 2,6-Disubstituted purine containing derivatives such as compounds 1, (±)-7e and β-L-(+)-2 showed the most potent inhibition of the parasite in vitro, with low micromolar IC50 values. These results are remarkable considering the anionic nature of nucleotide analogues, which are known to lack activity in cell culture experiments due to their scarce capacity to cross cell membranes. For the first time, we report the antimalarial activity of a carbocyclic methylphosphonate nucleoside with an L-like configuration.

Chemical Diversification of Carbocyclic Fluorinated Pyrimidine Nucleosides: Introducing 2′-Arabino Analogues and Ring Unsaturation

AbstractAnalogues of the canonical nucleosides have a longstanding presence and proven capability within medicinal chemistry and drug-discovery research. Herein, we report chemical diversification of carbocyclic pyrimidine nucleosides containing CF2 and CHF in place of the furanose oxygen to introduce ring unsaturation and 2′-epimers. Utilizing gram-scale access to 6′-(R)-monofluoro- and 6′-gem-difluorouridine, we explore the provision of 2′,3′-didehydro-2′,3′-dideoxy, and 1′,2′-didehydro-2′-deoxy analogues, alongside the first example of a 6′-(R)-fluoro arabino-carbauridine. Key stereochemistries and the presence of unsaturation are confirmed using X-ray crystallography and NMR, and an indicative conformational preference for a monofluoro 2′,3′-didehydro-2′,3′-dideoxy system is presented. This synthetic blueprint offers a potential to explore biological activity for these hitherto unavailable materials, including a direct comparison to established nucleoside analogue drugs.

Structure-Activity Relationships of Truncated 1'-Homologated Carbaadenosine Derivatives as New PPARγ/δ Ligands: A Study on Sugar Puckering Affecting Binding to PPARs.

Peroxisome proliferator-activated receptors (PPARs) are associated with the regulation of metabolic homeostasis. Based on a previous report that 1'-homologated 4'-thionucleoside acts as a dual PPARγ/δ modulator, carbocyclic nucleosides 2-5 with various sugar conformations were synthesized to determine whether sugar puckering affects binding to PPARs. (S)-conformer 2 was synthesized using Charette asymmetric cyclopropanation, whereas (N)-conformer 3 was synthesized using stereoselective Simmons-Smith cyclopropanation. All synthesized nucleosides did not exhibit binding affinity to PPARα but exhibited significant binding affinities to PPARγ/δ. The binding affinity of final nucleosides to PPARγ did not differ significantly based on their conformation, but their affinity to PPARδ depended greatly on their conformation, correlated with adiponectin production. (N)-conformer 3h was discovered to be the most potent PPARδ antagonist with good adiponectin production, which exhibited the most effective activity in inhibiting the mRNA levels of LPS-induced IL-1β expression in RAW 264.7 macrophages, implicating its anti-inflammatory activity.

Biocatalytic synthesis of chiral five-membered carbasugars intermediates utilizing CV2025 ω-transaminase from Chromobacterium violaceum

(S)-4-(Hydroxymethyl)cyclopent-2-enone is a key intermediate in the synthesis of chiral five-membered carbasugars, which can be used to synthesize a large number of pharmacologically relevant carbocyclic nucleosides. Herein, CV2025 ω-transaminase from Chromobacterium violaceum was selected based on substrate similarity to convert ((1S,4R)-4-aminocyclopent-2-enyl)methanol to (S)-4-(hydroxymethyl)cyclopent-2-enone. The enzyme was successfully cloned, expressed in Escherichiacoli, purified and characterized. We show that it has R configuration preference in contrast with the conventional S preference. The highest activity was obtained below 60°C and at pH 7.5. Cations Ca2+ and K+ enhanced activity by 21% and 13%, respectively. The conversion rate reached 72.4% within 60min at 50°C, pH 7.5, using 0.5mM pyridoxal-5'-phosphate, 0.6μM CV2025, and 10mM substrate. The present study provides a promising strategy for preparing five-membered carbasugars economically and efficiently.

Synthesis of 4'-Substituted Carbocyclic Uracil Derivatives and Their Monophosphate Prodrugs as Potential Antiviral Agents.

Over the past decades, both 4'-modified nucleoside and carbocyclic nucleoside analogs have been under the spotlight as several compounds from either family showed anti-HIV, HCV, RSV or SARS-CoV-2 activity. Herein, we designed compounds combining these two features and report the synthesis of a series of novel 4'-substituted carbocyclic uracil derivatives along with their corresponding monophosphate prodrugs. These compounds were successfully prepared in 19 to 22 steps from the commercially available (-)-Vince lactam and were evaluated against a panel of RNA viruses including SARS-CoV-2, influenza A/B viruses and norovirus.

Conformationally Locked Carbocyclic Nucleosides Built on a 4'-Hydroxymethyl-3'-hydroxybicyclo[4.1.0]heptane Template. Stereoselective Synthesis and Antiviral Activity.

Two new families of enantiomerically pure carbocyclic nucleoside analogues based on a cyclohexane moiety with five chiral centers and a fused cyclopropyl ring have been synthesized. A highly regio- and stereoselective synthetic approach for the modular construction of the functionalized bicyclo[4.1.0]heptyl azide intermediate 6 has been established. Key steps to achieve this asymmetric synthesis involved highly diastereoselective allylic oxidation and hydroboration reactions. The first family of compounds, 1a,b and 2, presents different natural nucleobases, whereas the second one 3a-e bears functionalized 1,2,3-triazoles. These derivatives have been tested as antiviral agents, and compound 3d has shown to display moderate activity against coxsackie B4 virus.

Lewis Acid Catalyzed (3+2)‐Cycloadditions of Chiral Pyrimidinyl‐Substituted Cyclopropanes with Nitrosoarenes or Silyl Enol Ethers

AbstractChiral isoxazole and carbocyclic pyrimidine nucleoside analogues were synthesized via (3+2)‐cycloadditions of chiral pyrimidinyl‐substituted dimethyl cyclopropanedicarboxylates. In the presence of MgI2, (3+2)‐cycloadditions of chiral pyrimidinyl‐substituted cyclopropanes with nitrosoarenes afforded diverse chiral isoxazole pyrimidine nucleoside analogues in up to 78 % yield and 88–96 % ee. Using Nd(OTf)3 as the catalyst, the annulation reaction with silyl enol ethers generated a series of chiral carbocyclic pyrimidine nucleoside analogues in up to 64 % yield, >20 : 1 dr, and 87–96 % ee. The proposed methods either reduced or avoided partial racemization.

Synthesis of Truncated Carbocyclic Nucleosides Using 5′‐Deoxy‐5′‐Heteroarylsulfonylnucleosides

This article describes the detailed protocol for the synthesis of "truncated" carbocyclic nucleosides with a cyclopentene core and without a 4'-hydroxymethyl group. The synthesis was performed using 5'-deoxy-5'-heteroarylsulfonylnucleosides, which were prepared by the 5'-O-mesylation of the appropriately protected nucleosides, followed by a nucleophilic substitution with heteroarylthiols and the oxidation of the resulting 5'-S-heteroaryl-5'-thionucleosides. The treatment of the 5'-deoxy-5'-heteroarylsulfonylnucleosides with 1,8-diazabicyclo[5.4.0]undec-7-ene affords the truncated carbocyclic nucleosides, presumably via a domino reaction involving the α-deprotonation of the heteroarylsulfone, elimination of the nucleobase, formation of an α,β-unsaturated sulfone, Michael addition of the nucleobase to the α,β-unsaturated sulfone, and an intramolecular Julia-Kocienski reaction. This protocol would be useful for the short-step synthesis of biologically active carbocyclic nucleosides. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Preparation of 5'-deoxy-5'-heteroarylsulfonylnucleosides Basic Protocol 2: Synthesis of truncated carbocyclic nucleosides.

Recent advances in the synthesis of 4′-truncated nucleoside phosphonic acid analogues

The synthesis of five series of 4′-truncated nucleoside phosphonic acid analogues is discussed in this review: (1) 4′-truncated furanose nucleoside phosphonic acid analogues; (2) 4′-truncated pyrrolidine nucleoside phosphonic acid analogues; (3) 4′-truncated carbocyclic nucleoside phosphonic acid analogues; (4) 4′-truncated isoxazole nucleoside phosphonic acid analogues; (5) 4′-truncated miscellaneous nucleoside phosphonic acid analogues. Five different ways are used to make the phosphonate moiety: (i) Michaelis-Arbuzov reaction of RX (X = Br, I, OTf) with trialkyl phosphate; (ii) Lewis acid catalyzed Michaelis-Arbuzov reaction of glycoside with trialkyl phosphite; (iii) nucleophilic addition of a dialkyl phosphite to a carbonyl group; (iv) direct coupling reaction with amino alkyl phosphonate; (v) de novo synthesis of phosphonated-isoxazole and 1,3-dioxolane heterocycles from phosphonated starting materials. Their biological activity results are briefly discussed.

Chemical Approaches to Carbocyclic Nucleosides.

Nucleoside analogues are at the forefront of antiviral therapy for last decades. To circumvent some of their limitations, based on their metabolism, and in order to improve their anti-viral potency and selectivity, several families of nucleoside analogues have been described through structural modifications at the sugar and heterocycles. The replacement of the oxygen of the nucleoside by a methylene has led to the family of carbocyclic (or cyclopentane) nucleoside analogues. Various potent anti-HIV and anti-HBV drugs belong to this family. Main syntheses of carbocyclic analogues of nucleosides used Diels-Alder reactions (in racemic or asymmetric series), but also started from carbohydrates (ribose, glucose), as a source of optically active compounds, which then had to be transformed into carbacycles under various conditions. The growing interest in carbocyclic nucleosides has led several groups, including ours, to develop new analogues and to explore novel routes. This article will review some of the recent chemistry developed on selected five-membered ring carbocyclic nucleosides.

Synthesis of fluorinated carbocyclic pyrimidine nucleoside analogues.

Analogues of the canonical nucleosides have a longstanding presence and proven capability within medicinal chemistry and drug discovery research. The synthesis reported herein successfully replaces furanose oxygen with CF2 and CHF in pyrimidine nucleosides, granting access to an alternative pharmacophore space. Key diastereoselective conjugate addition and fluorination methodologies are developed from chiral pool materials, establishing a robust gram-scale synthesis of 6'-(R)-monofluoro- and 6'-gem-difluorouridines. Vital intermediate stereochemistries are confirmed using X-ray crystallography and NMR analysis, providing an indicative conformational preference for these fluorinated carbanucleosides. Utilising these 6'-fluorocarbauridine scaffolds enables synthesis of related cytidine, ProTide and 2'-deoxy analogues alongside a preliminary exploration of their biological capabilities in cancer cell viability assays. This synthetic blueprint offers potential to explore fluorocarbanucleoside scaffolds, indicatively towards triphosphate analogues and as building blocks for oligonucleotide synthesis.

Synthesis and antiviral activity of 2'-deoxy-6'-substituted carbocyclic nucleosides.

A series of 2'-deoxy carbocyclic nucleosides characterized by various 6'-substitutions were synthesized and evaluated for their antiviral activities against three viruses, including hepatitis B virus (HBV), hepatitis C virus, and influenza virus. The in vitro antiviral assays indicated that these nucleosides only showed inhibitory activities against HBV, and the substituted groups at the 6' position significantly affected the activity. Among them, the guanosine analog 2b bearing a 6'-α-hydroxyl methyl group was the most potent compound with an EC50 value of 80nM. The present study provided useful information for the discovery of antiviral carbocyclic nucleosides.

Enantiomeric 4′-truncated 6′-fluoro-3-deazaneplanocin and its 3-bromo derivative: Synthesis and antiviral properties, including Ebola and Marburg

In seeking to increase the library of fluorine containing adenine-derived carbocyclic nucleoside antiviral candidates, d-like and l-like 6′-fluoro-3-deazaneplanocin and its 3-bromo derivative lacking the 4′-hydroxylmethylene substituent (2/3 and 4/5, respectively) are presented. Their synthesis was accomplished from d-ribose by developing a more facile precursor route than suggested by the literature. The 2/4d-like pair displayed significant anti-filo virial properties while the enantiomeric l-like congeners 3/5 were inactive. Target compounds 2/4 also were active towards measles and norovirus. The effect of 2/4 is further evidence of the role fluoro-derived adenine carbocyclic nucleoside can play in antiviral drug discovery. Furthermore, the simplicity of their synthesis lends them to more efficacious analogs and to scale-up optimization. There were no other relevant antiviral properties for 2/3 and 4/5 (except BK polyomavirus for 3/5).

Synthesis and Reactivity of Spirocarbocycles as Scaffolds for Nucleoside Analogues.

A novel class of substituted spiro[3.4]octanes can be accessed via a [2 + 2]-cycloaddition of dichloroketene on a readily prepared exo-methylene cyclopentane building block. This reaction sequence was found to be robust on a multigram scale and afforded a central spirocyclobutanone scaffold for carbocyclic nucleosides. The reactivity of this constrained building block was evaluated and compared to the corresponding 4'-spirocyclic furanose analogues. Density functional theory calculations were performed to support the observed selectivity in the carbonyl reduction of spirocyclobutanone building blocks. Starting from novel spirocyclic intermediates, we exemplified the preparation of an undescribed class of carbocyclic nucleoside analogues and provided a proof of concept for application as inhibitors for the protein methyltransferase target PRMT5.

From Heterocycles to Carbacycles: Synthesis of Carbocyclic Nucleoside Analogues from Enals and Hydroxylamines.

Substituted and stereochemically dense carbacycles can be prepared by sequential dipolar cycloaddition and reductive cleavage from enals and hydroxylamines. The reaction sequence proceeds with high efficiency for a wide variety of enals and hydroxylamines. The reaction is regio- and diastereoselective for the initial formation of a bridged bisisoxazolidine intermediate, which then undergoes quantitative double N-O cleavage to produce carbacycles as single diastereomers.