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Synthesis of phosphonate derivatives of 2'-deoxy-2'-fluorotetradialdose d-nucleosides and tetradialdose d-nucleosides.

ABSTRACT: Analogs of nucleosides and nucleotides represent a promising pool of potential therapeutics. This work describes a new synthetic route leading to 2'-deoxy-2'-fluorotetradialdose D-nucleoside phosphonates. Moreover, a new universal synthetic route leading to tetradialdose d-nucleosides bearing purine nucleobases is also described. All new compounds were tested as triphosphate analogs for inhibitory potency against a variety of viral polymerases. The fluorinated nucleosides were transformed to phosphoramidate prodrugs and evaluated in cell cultures against various viruses including influenza and SARS-CoV-2.

SUBMITTER: Lasek T

PROVIDER: S-EPMC8049856 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Synthesis of C-glycosyl phosphonate derivatives of 4-amino-4-deoxy-?-?-arabinose.

Project description:The incorporation of basic substituents into the structurally conserved domains of cell wall lipopolysaccharides has been identified as a major mechanism contributing to antimicrobial resistance of Gram-negative pathogenic bacteria. Inhibition of the corresponding enzymatic steps, specifically the transfer of 4-amino-4-deoxy-?-arabinose, would thus restore the activity of cationic antimicrobial peptides and several antimicrobial drugs. C-glycosidically-linked phospholipid derivatives of 4-amino-4-deoxy-?-arabinose have been prepared as hydrolytically stable and chain-shortened analogues of the native undecaprenyl donor. The C-phosphonate unit was installed via a Wittig reaction of benzyl-protected 1,5-arabinonic acid lactone with the lithium salt of dimethyl methylphosphonate followed by an elimination step of the resulting hemiketal, leading to the corresponding exo- and endo-glycal derivatives. The ensuing selective monodemethylation and hydrogenolysis of the benzyl groups and reduction of the 4-azido group gave the ?-?-anomeric arabino- and ribo-configured methyl phosphonate esters. In addition, the monomethyl phosphonate glycal intermediates were converted into n-octyl derivatives followed by subsequent selective removal of the methyl phosphonate ester group and hydrogenation to give the octylphosphono derivatives. These intermediates will be of value for their future conversion into transition state analogues as well as for the introduction of various lipid extensions at the anomeric phosphonate moiety.

| S-EPMC6964659 | biostudies-literature

Synthesis of 5'-methylene-phosphonate furanonucleoside prodrugs: application to D-2'-deoxy-2'-?-fluoro-2'-?-C-methyl nucleosides.

Project description:A new and facile synthetic pathway to metabolically stable 5'-methylene-bis(pivaloyloxymethyl)(POM)phosphonate furanonucleoside prodrugs is reported. The key step involves a Horner-Wadsworth-Emmons reaction of a tetra(pivaloyloxymethyl) bisphosphonate salt with appropriately protected 5'-aldehydic nucleosides. This efficient approach was applied for the synthesis HCV related 2'-deoxy-2'-?-fluoro-2'-?-C-methyl nucleosides.

| S-EPMC3470451 | biostudies-literature

Synthesis of 2'-deoxy-9-deaza nucleosides using Heck methodology.

Project description:During the synthesis of a series of 2'-deoxy-9-deaza nucleosides using Heck methodology, the necessity for a pyrrole protecting group was discovered. The results of this brief study revealed that the benzyloxymethyl (BOM) group proved optimal, and Heck coupling using Jeffery conditions increased the coupling yield significantly. The results are reported herein.

| S-EPMC5638437 | biostudies-literature

Synthesis of conformationally locked L-deoxythreosyl phosphonate nucleosides built on a bicyclo[3.1.0]hexane template.

Project description:Two conformationally locked versions of l-deoxythreosyl phosphonate nucleosides (2 and 3) were synthesized to investigate the preference of HIV reverse transcriptase for a conformation displaying either a fully diaxial or fully diequatorial disposition of substituents. Synthesis of the enantiomeric 4-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-2-ol carbocyclic nucleoside precursors (diaxially disposed) proceeded straightforwardly from commercially available (1R,4S)-4-hydroxy-2-cyclopent-2-enyl-1-yl acetate employing a hydroxyl-directed Simmons-Smith cyclopropanation that culminated with a Mitsunobu coupling of the purine base. For the more complicated 1-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-3-ol carbocyclic nucleoside precursors (diequatorially disposed), the obligatory linear approach required the syntheses of key 1-aminobicyclo[3.1.0.]hexan-3-yl benzoate precursors that were assembled via the amide variant of the Kulinkovich reaction involving the intramolecular cyclopropanation of a substituted ?-vinylamide. Completion of the purine ring was achieved by conventional approaches but with much improved yields through the use of a microwave reactor. The syntheses of the phosphonates and the corresponding diphosphates were achieved by conventional means. None of the diphosphates, which were supposed to act as nucleoside triphosphate mimics, could compete with dATP even when present in a 10-fold excess.

| S-EPMC3041872 | biostudies-literature

Synthesis and P2Y receptor activity of nucleoside 5'-phosphonate derivatives.

Project description:Ribose-based nucleoside 5'-diphosphates and triphosphates and related nucleotides were compared in their potency at the P2Y receptors with the corresponding nucleoside 5'-phosphonate derivatives. Phosphonate derivatives of UTP and ATP activated the P2Y(2) receptor but were inactive or weakly active at P2Y(4) receptor. Uridine 5'-(diphospho)phosphonate was approximately as potent at the P2Y(2) receptor as at the UDP-activated P2Y(6) receptor. These results suggest that removal of the 5'-oxygen atom from nucleotide agonist derivatives reduces but does not prevent interaction with the P2Y(2) receptor. Uridine 5'-(phospho)phosphonate as well as the 5'-methylenephosphonate equivalent of UMP were inactive at the P2Y(4) receptor and exhibited maximal effects at the P2Y(2) receptor that were 50% of that of UTP suggesting novel action of these analogues.

| S-EPMC2721324 | biostudies-literature

Synthesis, Bioactivity and Molecular Docking of Nereistoxin Derivatives Containing Phosphonate.

Project description:Novel nereistoxin derivatives containing phosphonate were synthesized and characterized via 31P, 1H and 13C NMR and HRMS. The anticholinesterase activity of the synthesized compounds was evaluated on human acetylcholinesterase (AChE) using the in vitro Ellman method. Most of the compounds exhibited good inhibition of acetylcholinesterase. All of these compounds were selected to assess their insecticidal activity (in vivo) against Mythimna separata Walker, Myzus persicae Sulzer and Rhopalosiphum padi. Most of the tested compounds displayed potent insecticidal activity against these three species. Compound 7f displayed good activity against all three insect species, showing LC50 values of 136.86 μg/mL for M. separata, 138.37 μg/mL for M. persicae and 131.64 μg/mL for R. padi. Compound 7b had the highest activity against M. persicae and R. padi, with LC50 values of 42.93 μg/mL and 58.19 μg/mL, respectively. Docking studies were performed to speculate the possible binding sites of the compounds and explain the reasons for the activity of the compounds. The results showed that the compounds had lower binding energies with AChE than with the acetylcholine receptor (AchR), suggesting that compounds are more easily bound with AChE.

| S-EPMC10305189 | biostudies-literature

Novel 1'-homo-<i>N</i>-2'-deoxy-α-nucleosides: synthesis, characterization and biological activity.

Project description:For the first time, a series of novel 1'-homo-N-2'-deoxy-α-nucleosides containing natural nucleobases as well as 5-fluoro and 5-iodopyrimidine analogs have been synthesized in an efficient manner. Additionally, a high yield protocol for the assembly of a dimeric scaffold containing two sugar moieties linked to the N-1 and N-3 positions of a single pyrimidine base has been accomplished. The structures of the novel homonucleosides were established by a single crystal X-ray structure of 1'-homo-N-2'-deoxy-α-adenosine and NMR studies. The biological activity of these 1'-homo-N-2'-deoxy-α-nucleosides as antiviral (HIV-1 and HBV) and cytotoxic studies was measured in multiple cell systems. The unique structure and easy accessibility of these compounds may allow their use in the design of new nucleoside analogs with potential biological activity and as a scaffold for combinatorial chemistry.

| S-EPMC8486263 | biostudies-literature

Synthesis, cytotoxicity, DNA binding and apoptosis of rhein-phosphonate derivatives as antitumor agents.

Project description:Several rhein-phosphonate derivatives (5a-c) were synthesized and evaluated for in vitro cytotoxicity against HepG-2, CNE, Spca-2, Hela and Hct-116 cell lines. Some compounds showed relatively high cytotoxicity. Especially compounds 5b exhibited the strongest cytotoxicity against HepG-2 and Spca-2 cells (IC50 was 8.82 and 9.01 µM), respectively. All the synthesized compounds exhibited low cytotoxicity against HUVEC cells. Further experiments proved that 5b could disturb the cell cycle in HepG-2 cells and induce apoptosis. In addition, the binding properties of a model conjugate 5b to DNA were investigated by methods (UV-Vis, fluorescence, CD spectroscopy). Results indicated that 5b showed moderate ability to interact ct-DNA.

| S-EPMC3676791 | biostudies-literature

Organometallic Nucleosides: Synthesis and Biological Evaluation of Substituted Dicobalt Hexacarbonyl 2'-Deoxy-5-oxopropynyluridines.

Project description:Reactions of dicobalt octacarbonyl [Co2(CO)8] with 2'-deoxy-5-oxopropynyluridines and related compounds gave dicobalt hexacarbonyl nucleoside complexes (83-31?%). The synthetic outcomes were confirmed by X-ray structure determination of dicobalt hexacarbonyl 2'-deoxy-5-(4-hydroxybut-1-yn-1-yl)uridine, which exhibits intermolecular hydrogen bonding between a modified base and ribose. The electronic structure of this compound was characterized by the DFT calculations. The growth inhibition of HeLa and K562 cancer cell lines by organometallic nucleosides was examined and compared to that by alkynyl nucleoside precursors. Coordination of the dicobalt carbonyl moiety to the 2'-deoxy-5-alkynyluridines led to a significant increase in the cytotoxic potency. The cobalt compounds displayed antiproliferative activities with median inhibitory values (IC50) in the range of 20 to 80??m for the HeLa cell line and 18 to 30??m for the K562 cell line. Coordination of an acetyl-substituted cobalt nucleoside was expanded by using the 1,1-bis(diphenylphosphino)methane (dppm) ligand, which exhibited cytotoxicity at comparable levels. The formation of reactive oxygen species in the presence of cobalt compounds was determined in K562 cells. The results indicate that the mechanism of action for most antiproliferative cobalt compounds may be related to the induction of oxidative stress.

| S-EPMC5838391 | biostudies-other

An efficient synthesis tetrazole and oxadiazole analogues of novel 2'-deoxy-C-nucleosides and their antitumor activity.

Project description:Various tetrazole and oxadiazole C-nucleoside analogues were synthesized starting from pure α- or β-glycosyl-cyanide. The synthesis of glycosyl-cyanide as key precursor was optimized on gram-scale to furnish crystalline starting material for the assembly of C-nucleosides. Oxadizole C-nucleosides were synthesized via two independent routes. First, the glycosyl-cyanide was converted into an amidoxime which upon ring closure offered an alternative pathway for the assembly of 1,2,4-oxadizoles in an efficient manner. Second, both anomers of glycosyl-cyanide were transformed into tetrazole nucleosides followed by acylative rearrangement to furnish 1,3,4-oxadiazoles in high yields. These protocols offer an easy access to otherwise difficult to synthesize C-nucleosides in good yield and protecting group compatibility. These C-nucleosides were evaluated for their antitumor activity. This work paves a path for facile assembly of library of new chemical entities useful for drug discovery.

| S-EPMC7576186 | biostudies-literature

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