Synthesis of Nucleoside-like Molecules from a Pyrolysis Product of Cellulose and Their Computational Prediction as Potential SARS-CoV-2 RNA-Dependent RNA Polymerase Inhibitors.

(1R,5S)-1-Hydroxy-3,6-dioxa-bicyclo[3.2.1]octan-2-one, available by an efficient catalytic pyrolysis of cellulose, has been applied as a chiral building block in the synthesis of seven new nucleoside analogues, with structural modifications on the nucleobase moiety and on the carboxyl- derived unit. The inverted configuration by Mitsunobu reaction used in their synthesis was verified by 2D-NOESY correlations, supported by the optimized structure employing the DFT methods. An in silico screening of these compounds as inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase has been carried out in comparison with both remdesivir, a mono-phosphoramidate prodrug recently approved for COVID-19 treatment, and its ribonucleoside metabolite GS-441524. Drug-likeness prediction and data by docking calculation indicated compound 6 [=(3S,5S)-methyl 5-(hydroxymethyl)-3-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)tetrahydrofuran-3-carboxylate] as the best candidate. Furthermore, molecular dynamics simulation showed a stable interaction of structure 6 in RNA-dependent RNA polymerase (RdRp) complex and a lower average atomic fluctuation than GS-441524, suggesting a well accommodation in the RdRp binding pocket.

Synthesis, Structural Characterization, and Biological Activity of New Pyrazolo[4,3-e][1,2,4]triazine Acyclonucleosides.

A series of new pyrazolo[4,3-e][1,2,4]triazine acyclonucleosides 2-5 and 8 were prepared and evaluated for their anticancer activity against human cancer cell lines (MCF-7, K-562) and CDK2/E, as well as Abl protein kinases inhibitors. Lipophilicity of the compounds was determined using C-18 and immobilized artificial membrane (IAM) chromatography. In order to confirm the molecular structures and synthesis pathway of new acyclonucleosides, X-ray analysis was performed for model compound 3. Theoretical calculations at the DFT/B3LYP/6-311++G(d,p) level were used for the characterization of electronic structures of 1-8. The potential antiviral activity of acyclonucleosides 2-8 was tested in silico using molecular docking method.

Evaluation of tetraether lipid-based liposomal carriers for encapsulation and retention of nucleoside-based drugs.

Although liposomal nanoparticles are one of the most versatile class of drug delivery systems, stable liposomal formulation of small neutral drug molecules still constitutes a challenge due to the low drug retention of current lipid membrane technologies. In this study, we evaluate the encapsulation and retention of seven nucleoside analog-based drugs in liposomes made of archaea-inspired tetraether lipids, which are known to enhance packing and membrane robustness compared to conventional bilayer-forming lipids. Liposomes comprised of the pure tetraether lipid generally showed improved retention of drugs (up to 4-fold) compared with liposomes made from a commercially available diacyl lipid. Interestingly, we did not find a significant correlation between the liposomal leakage rates of the molecules with typical parameters used to assess lipophilicity of drugs (such logD or topological polar surface area), suggesting that specific structural elements of the drug molecules can have a dominant effect on leakage from liposomes over general lipophilic character.

Synthesis and complementary self-association of novel lipophilic π-conjugated nucleoside oligomers.

A series of lipophilic nucleosides comprising natural and non-natural bases that are π-conjugated to a short oligophenylene-ethynylene fragment has been synthesized. These bases comprise guanosine, isoguanosine, and 2-aminoadenosine as purine heterocycles, and cytidine, isocytosine and uridine as complementary pyrimidine bases. The hydrogen-bonding dimerization and association processes between complementary bases were also studied by (1)H NMR and absorption spectroscopy in order to obtain the relevant association constants.

Solid-phase synthesis of (poly)phosphorylated nucleosides and conjugates.

Succinyl-cycloSal-phosphate triesters of ribo- and 2'-deoxyribonucleosides were attached to aminomethyl polystyrene as an insoluble solid support and reacted with phosphate-containing nucleophiles yielding nucleoside di- and triphosphates, nucleoside diphosphate sugars, and dinucleoside polyphosphates in high purity after cleavage from the solid support. Here, reactive cycloSal-phosphate triesters were used as immobilized reagents that led to a generally applicable method for the efficient synthesis of phosphorylated biomolecules and phosphate-bridged bioconjugates.

[Design, synthesis and evaluation of polyamide-nucleoside hybrids and oligonucleotides conjugated hybrid as a novel gene expression control compound].

On the basis of reports that a minor groove binder pyrrolepolyamide can interfere with gene expression by the sequence-specific recognition of DNA, we expected that nucleoside bearing a pyrrolepolyamide would be able to regulate gene expression. Therefore, we designed and synthesized the pyrrolepolyamide-adenosine (Hybrid 1) and -2'-deoxyguanosine hybrids (Hybrid 2 and Hybrid 3) as lead compounds for gene expression control compounds. The pyrrolepolyamide frame of Hybrid 2 and Hybrid 3 combines at the 2-exocyclic amino group of the 2'-deoxyguanosine by a linker and the 2-exocyclic amino group of guanine exists in the minor groove side of the duplex. Hybrid 2 is the 2'-deoxyguanosine-pyrrolepolyamide hybrid using the 3-aminopropionyl linker, while Hybrid 3 uses the 3-aminopropyl linker. An evaluation of the DNA binding sequence selectivity was performed by analysis of T(m) values and CD spectra, using distamycin A as a contrast. Hybrid 3 has provided more excellent sequence-distinguishable ability than other hybrids and Distamycin A. Moreover, on the basis of these results, we synthesized oligonucleotides conjugated to Hybrid 4, which is stable under conditions of DNA oligonucleotide solid phase synthesis, arranged from Hybrid 3. From T(m) values and CD spectral analysis, it was found that oligonucleotides conjugating Hybrid 4 possess high recognition ability and very high binding ability for the DNA that includes the pyrrolepolyamide binding sequence.

Was adenine the first purine?

Oligomerization of HCN (1 molar) in the presence of added formaldehyde (0.5 molar) produced an order of magnitude more 8-hydroxymethyladenine than adenine or any other biologically significant purine. This result suggests that on the prebiotic Earth, nucleoside analogs may have been synthesized directly in more complex mixtures of HCN with other aldehydes.

Solid-phase synthesis of heterocyclic nucleoside analogues: substituted uracils tethered to isoxazoles, isoxazolines, and triazoles from a selenopolystyrene resin.

A heterocyclic nucleoside analogue library of uracils N1 tethered to isoxazoles, isoxazolines, and triazoles and uracil N3 tethered to isoxazolines and isoxazoles was constructed by solid-phase organic synthesis. This strategy opens the way for the generation of small libraries of heterocyclic nucleoside analogues for biological screening.

Selective diphosphorylation, dithiodiphosphorylation, triphosphorylation, and trithiotriphosphorylation of unprotected carbohydrates and nucleosides.

[chemical reaction: see text]. Aminomethyl polystyrene resin-bound linkers of p-acetoxybenzyl alcohol were subjected to reactions with diphosphitylating and triphosphitylating reagents to yield the corresponding polymer-bound diphosphitylating and triphosphitylating reagents, respectively. A number of unprotected carbohydrates and nucleosides were reacted with the polymer-bound reagents. Oxidation with tert-butyl hydroperoxide or sulfurization with Beaucage's reagent, followed by removal of cyanoethoxy group with DBU and the acidic cleavage, respectively, afforded only one type of monosubstituted nucleoside and carbohydrate diphosphates, dithiodiphosphates, triphosphates, and trithiotriphosphates with high regioselectivity.

Carbocyclic dinucleoside polyphosphonates: interaction with HIV reverse transcriptase and antiviral activity.

Carbocyclic alpha, gamma-bis(nucleoside)-5,5'-triphosphonates and alpha, delta-bis(nucleoside)-5,5'-tetraphosphonates (Ap4A and Gp4G) analogues were shown to be a new type of terminating substrate of HIV reverse transcriptase. They effectively inhibited the DNA synthesis catalyzed by this enzyme in model cell-free systems, but their antiviral activity both in Rat1 fibroblast cell culture bearing MLV reverse transcriptase and in HIV-infected MT-4 cells was low. When a liposome delivery system was used, the antiviral efficacy of the compounds under study was increased.

Photochemistry on soluble polymer supports: synthesis of nucleosides.

[reaction: see text] A new soluble polymer support synthesis of nucleosides is described. The photochemical ring expansion of cyclobutanones in the presence of poly(ethylene glycol) (PEG) results in polymer-supported ribosides. These photoadducts can be cleaved from the polymer under Vorbrüggen coupling conditions with TMS-protected purines and pyrimidines to give ribonucleosides. The method has been extended to include modified PEGs with dendritic end-groups in order to improve the loading levels for these coupling reactions.

Synthesis and analysis of nucleosides bearing pyrrolepolyamide binding to DNA.

An efficient synthesis of adenosine bearing pyrrolepolyamide 1 was achieved by coupling of 3 with 2. The CD spectra obtained at several [ligand ]/[duplex] ratios allowed verification of the formation complex of the DNA duplex [d(CGCAAATTGGC)/d(GCCAATTTGCG)] with 1.

Comparative study of liponucleosides in Langmuir monolayers as cell membrane models.

Liponucleosides may assist the anchoring of nucleic acid nitrogen bases into biological membranes for tailored nanobiotechnological applications. To this end precise knowledge about the biophysical and chemical details at the membrane surface is required. In this paper, we used Langmuir monolayers as simplified cell membrane models and studied the insertion of five lipidated nucleosides. These molecules varied in the type of the covalently attached lipid group, the nucleobase, and the number of hydrophobic moieties attached to the nucleoside. All five lipidated nucleosides were found to be surface-active and capable of forming stable monolayers. They could also be incorporated into dipalmitoylphosphatidylcholine (DPPC) monolayers, four of which induced expansion in the surface pressure isotherm and a decrease in the surface compression modulus of DPPC. In contrast, one nucleoside possessing three alkyl chain modifications formed very condensed monolayers and induced film condensation and an increase in the compression modulus for the DPPC monolayer, thus reflecting the importance of the ability of the nucleoside molecules to be arranged in a closely packed manner. The implications of these results lie on the possibility of tuning nucleic acid pairing by modifying structural characteristics of the liponucleosides.

Synthesis of nucleoside mono-, di-, and triphosphoramidates from solid-phase cyclosaligenyl phosphitylating reagents.

Chloromethyl polystyrene resin was reacted with 5-hydroxysalicylaldehyde in the presence of potassium carbonate to afford polymer-bound 2-hydroxybenzaldehyde. Subsequent reduction with borane solution produced polymer-bound 2-hydroxybenzyl alcohol. The reaction of immobilized 2-hydroxybenzyl alcohol with appropriate phosphitylating reagents yielded solid-phase cycloSaligenyl mono-, di-, and triphosphitylating reagents, which were reacted with unprotected nucleosides, followed by iodine oxidation, deprotection of cyanoethoxy groups, and the basic cleavage, respectively, to afford 5'-O-nucleoside mono-, di-, and triphosphoramidates in 52-73% overall yield.

Solid-supported diphosphitylating and triphosphitylating reagents for nucleoside modification.

This unit describes procedures for synthesis of diphosphitylating and triphosphitylating reagents. The synthesized reagents are first immobilized on appropriate polymer-bound linkers. Rigid and sterically hindered polymer-bound diphosphitylating and triphosphitylating reagents are then reacted selectively with the 5'-hydroxyl group of nucleosides in the presence of excess nucleosides. Typical oxidation with tert-butyl hydroperoxide, deprotection, and final cleavage of the products from the resins using a trifluoroacetic acid cocktail afford various nucleoside 5'-O-diphosphate and nucleoside 5'-O-triphosphate analogs. The use of the diphosphitylating and polymer-bound diphosphitylating reagents in preparation of oligodeoxynucleotides containing diphosphodiester internucleotide bridges is also described. This solid-phase strategy allows for the synthesis of the phosphorylated compounds without the need for nucleoside phosphate precursors, protected nucleosides, or purification of intermediates.

About a formamide-based origin of informational polymers: syntheses of nucleobases and favourable thermodynamic niches for early polymers.

Formamide NH(2)CHO chemistry provides a unitary frame into which several pieces of the origin-of-life puzzle may be adjusted. Synthetic processes were uncovered which, starting from formamide and prebiotically easily available common catalysts, yield all the necessary nucleic bases precursors, including acyclonucleosides. Formamide allows phosphorylations and trans-phosphorylations, favours the micellar aggregation of surfactants and, most importantly, determines conditions in which the formation of nucleic polymers is thermodynamically favoured. In the detected conditions, the phosphoester bonds are more stable in the polymeric than in the monomeric form, thus allowing formation and survival of informational nucleic polymers.

Application of a solid-phase beta-triphosphitylating reagent in the synthesis of nucleoside beta-triphosphates.

A beta-triphosphitylating reagent was subjected to reaction with aminomethyl polystyrene resin-bound p-acetoxybenzyl alcohol to yield the corresponding polymer-bound beta-triphosphitylating reagent. The solid-phase reagent was reacted with unprotected nucleosides (e.g., 3'-azido-3'-deoxythymidine, cytidine, thymidine, uridine, inosine, or adenosine) in the presence of 1H-tetrazole. Polymer-bound nucleosides underwent oxidation with t-butyl hydroperoxide, deprotection of cyanoethoxy groups with DBU, and the acidic cleavage, respectively, to afford only monosubstituted 5'-O-beta-triphosphorylated nucleosides.

Synthesis and interaction studies of oligo and polyamino acids derivatives containing nucleosides.

Nucleic acid analogs of L-lysine derivatives containing uridine and/or adenosine were synthesized. As dimer models, Lys(Urd)-Lys(Urd) and Lys(Urd)-Lys(Ado) were prepared by activated ester method. These dimers were found to form complex with Poly A, which was observed from hypochromicity of UV spectra. Furthermore poly-L-lysine derivative containing uridine was also prepared. The maximum hypochromicity value of this polymer model with PolyA was higher than that of dimer models.

Controllable regioselective enzymatic synthesis of polymerizable 5'-O-vinyl- and 3'-O-vinyl-nucleoside analogues in acetone.

An efficient synthesis of polymerizable 3'- and 5'-O-acyl-nucleoside derivatives has been developed from inosine and 2'-deoxyuridine by enzyme-catalyzed regioselective acylation with divinyl dicarboxylates. In acetone, Lipozyme (immobilized lipase from Mucor miehei) gave 5'-O-acyl-nucleoside products, and PPL (lipase from porcine pancreas) provided 3'-O-acyl-nucleoside products.