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Protected N-branched nucleoside phosphonates containing adenine and thymine bases were prepared as the monomers for the introduction of aza-acyclic nucleotide units into modified oligonucleotides. The phosphotriester and phosphoramidite methods were used for the incorporation of modified and natural units, respectively. The solid phase synthesis of a series of nonamers containing one central modified unit was successfully performed in both 3'→5' and 5'→3' directions. Hybridization properties of the prepared oligoribonucleotides and oligodeoxyribonucleotides were evaluated. The measurement of thermal characteristics of the complexes of modified nonamers with the complementary strand revealed a considerable destabilizing effect of the introduced units. We also examined the substrate/inhibitory properties of aza-acyclic nucleoside phosphono-diphosphate derivatives (analogues of nucleoside triphosphates) but neither inhibition of human and bacterial DNA polymerases nor polymerase-mediated incorporation of these triphosphate analogues into short DNA was observed.

The synthesis of the novel nucleotide analogues 5'-deoxynucleoside-5'-S-methylphosphonates, starting from 5'-deoxy-5'-haloribonucleosides, 5'-O-tosylribonucleosides, and 2'-O-triflylnucleosides, is described. The phosphonothiolation of these compounds was achieved using S-(diisopropylphosphonomethyl)isothiouronium tosylate, a new, odourless, and efficient equivalent of mercaptomethylphosphonate. The thiolate anion of mercaptomethylphosphonate was generated in situ from the isothiouronium salt in both protic and aprotic solvents using two equivalents of sodium iso-propoxide. The prepared nucleoside 5'-S-methylphosphonates were deprotected, and the free phosphonic acids were transformed into diphosphoryl derivatives (the NTP analogues). Both mononucleotides and NTP analogues were studied as substrates/inhibitors of several enzymes that are involved in the nucleoside/nucleotide metabolism.

Structurally diverse, sugar-modified, thymine-containing nucleoside phosphonic acids were evaluated for their ability to inhibit thymidine phosphorylase (TP, EC 2.4.2.4) purified from spontaneous T-cell lymphomas of an inbred Sprague-Dawley rat strain. From a large set of tested compounds, among them a number of pyrrolidine-based derivatives, 10 nucleotide analogues with IC(50) values below 1 microM were selected. Out of them, four compounds strongly inhibited the enzyme with IC(50) values lying in a range of 11-45 nM. These most potent compounds might be bi-substrate analogues., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Among the structurally diverse nucleoside phosphonic acids, several compounds possessing strong antiviral properties have been found. Our effort in this area was focused to the synthesis of novel compounds - pyrrolidine-based nucleoside phosphonic acids and their derivatives.

A number of structurally diverse nucleoside phosphonic acids have been tested against human recombinant thymidine phosphorylase and human platelets supernatant using 2'-deoxy-5-nitrouridine as the substrate. We have selected several inhibitors working at micromolar level as lead structures for further evaluation.

A novel series of racemic piperidin-3-yl and piperidin-4-yl derivatives of nucleobases and their phosphonate derivatives were prepared.

Novel seven-membered nucleoside phostones were prepared by the reaction of chlorodiethyl phosphite with 3',5'-acetals or ketals derived from xylo-dT. A mechanism for the ring enlargement was proposed, and support for it was provided by ab initio calculations.

The present work relates to the synthesis of pyrrolidine nucleoside analogs. Starting from malic acid, we have elaborated a high-yield synthesis of racemic and enantiomeric N-protected 3-pyrrolidinols and their O-mesyl derivatives as key compounds for alkylations of purine and pyrimidine nucleobases. On varying base and solvent, we have found conditions providing both satisfactory N-/O-regioisomeric ratio and acceptable yield for pyrimidine compounds.

Cellular 5′‐nucleotidases, enzymes regulating nucleotide/nucleoside pools, are capable of dephosphorylating phosphomonoesters of important nucleoside analogue drugs, thus decreasing their therapeutic efficacy. Human cytosolic (cdN) as well as mitochondrial (mdN) variants of this enzyme represent interesting targets for development of inhibitory compounds. In this work, bisphosphonate nucleoside derivatives were designed by using a structure‐based approach. A second phosphonate group was attached onto a base moiety and by optimization of the linker an increased inhibitor potency towards mdN and cdN was attained. The best compound exhibited inhibition of both enzymes in a nanomolar range, making it the most potent inhibitor of these enzymes prepared to date. In addition, the compounds showed selectivity towards the cdN variant. A series of crystal structures were solved for several inhibitors in the complex with mdN or cdN that provided a structural basis for understanding the inhibition profile of bisphosphonate compounds. By using a structure‐based approach, bisphosphonate nucleoside derivatives have been designed that act as potent inhibitors of human cytosolic and mitochondrial 5′‐nucleotidases. [ABSTRACT FROM AUTHOR]

Suitably protected (R)‐ and (S)‐HPEP {9‐[3‐hydroxy‐2‐(phosphonoethoxy)propyl]} derivatives containing adenine and thymine nucleobases were prepared as monomers for the introduction of acyclic nucleotide units into oligonucleotides. The solid phase synthesis of a series of ribo and 2′‐deoxyribo nonamers containing (R)‐HPEP and (S)‐HPEP units was successfully performed in both 5′ → 3′ and 3′ → 5′ directions. The measurement of thermal characteristics of the complexes of modified nonamers with complementary DNA and RNA strands revealed a general destabilizing effect of the introduced acyclic units on the thermal stability, but in several cases [modif.RNA*RNA and modif.DNA*RNA with (S)‐HPEPA units], the duplexes were characterized in terms of Tm values. A solid‐phase synthesis afforded a series of ribo and 2′‐deoxyribo nonamers containing acyclic nucleotide units. A general destabilizing effect of the introduced acyclic units on the thermal stability of complexes of modified nonamers with the complementary DNA and RNA strands was observed, but in cases with (S)‐HPEPA units, the duplexes were characterized in terms of Tm values. [ABSTRACT FROM AUTHOR]

We report on a new analogue of locked cyclohexane nucleic acids that contains an adenine nucleobase at an alternative position and which resembles homo-DNA. The crucial locked carbocyclic nucleoside monomer was prepared with high enantioselectivity and was subsequently incorporated into a pair of modified oligonucleotides that were subjected to hybridization studies. [ABSTRACT FROM AUTHOR]

Taurine (2-aminoethanesulfonic acid) is a representative substructure in biologically active compounds, but can raise difficulties in direct coupling reactions. In this study, the synthesis of taurine-derived sulfonic acids and analogous aromatic sulfonic acids was accomplished by a performic acid promoted oxidation of corresponding symmetrical disulfide precursors. In some of the products, the taurine or sulfanilic acid nitrogen atom is incorporated in a heterocyclic scaffold or part of a peptide bond in dipeptide mimetics. [ABSTRACT FROM AUTHOR]

New isoelectronic, non-isosteric phosphonate analogues of nucleoside 5'-phosphates featuring the phosphorus moiety directly attached on the sugar ring in the C4' position are described. The analogues were synthesised by a nucleosidation reaction from tetrofuranosyl phosphonate synthons and silylated nucleobases. The pyrimidine compounds with erythro and threo configuration in both D- and L-series were prepared, and the structures were assigned by NMR spectroscopy. The results of NMR conformational studies show that all calculated conformers have a maximum pucker in the range typical for nucleosides. In all compounds, the S-type conformer is preferred and is more significant in α-D-threo-compounds. Studies on inhibition of thymidine phosphorylase revealed that one of the prepared phosphonic acids was a competitive inhibitor of the enzyme (Ki = 4 μM). [ABSTRACT FROM AUTHOR]

Adenine-based, regioisomeric nucleoside phosphonates with ribo, xylo and arabino configuration were synthesized in the protected form suitable for the phosphotriester-like, solid-phase synthesis of oligonucleotides. Phosphonate moiety was protected by 4-methoxy-1-oxido-2-picolyl group and the furanose hydroxyl by the dimethoxytrityl group. [ABSTRACT FROM AUTHOR]

The synthesis of monomers (S)-1, (R)-1 and 2 derived from (5′S)-, (5′R)-2′-deoxythymidine-5′-C-phosphonic acids and 2′,5′-dideoxythymidine-5′-C-phosphonic acids was elaborated. The protection of the 5′-hydroxyl by the methoxycarbonyl group was a key step of the synthesis. Prepared monomers were used for the solid-phase assembly of several types oligothymidylate 15-mers (S)-3, (S)-4, (S)-5, (R)-4 and (R)-5 containing the chiral 3′-O-P-CH(OH)-5″ internucleotide linkage. Their hybridization properties with dA15 and rA15 were studied as well as their resistance against nuclease cleavage. [ABSTRACT FROM AUTHOR]

A novel α- and β-configured pyrrolidine nucleoside phosphonates in adenine series were synthesized from trans-4-hydroxy-L-proline as starting material. d(ApA) analogues were also prepared and studied with respect to their hybridization properties with polyU. [ABSTRACT FROM AUTHOR]

Abstract: Straightforward, high-yielding syntheses of 3′-deoxy-3′,4′-didehydronucleoside-5′-aldehydes and 3′-deoxy-3′,4′-didehydronucleosides starting from 2′,3′-O-orthoester derivatives of ribonucleosides are described. [ABSTRACT FROM AUTHOR]

Purine and pyrimidine 4′-alkoxy-2′-deoxynucleosideswere efficiently prepared from nucleoside 4′-5′-enolacetates in three steps by N-iodosuccinimide promotedalkoxylation, hydrolysis, and reduction followed by conversion tophosphoramidite monomers for the solid-phase synthesis of the oligonucleotides.Fully modified 4′-alkoxyoligodeoxynucleotides, which are characterizedby a prevalent N-type (RNA-like) conformation, exhibitedsuperior chemical and nuclease resistance as well as excellent hybridizationproperties with a strong tendency for RNA-selective hybridization,suggesting a potential application of 4′-alkoxy-oligodeoxynucleotidesin antisense technologies. [ABSTRACT FROM AUTHOR]

Abstract: Novel phosphanucleosides containing a 3-hydroxy-1-hydroxymethylphospholane 1-oxide ring were synthesized as compounds with potential biological activity. A double Arbuzov reaction was employed to prepare a phospholene precursor, which was then converted into an epoxide and subsequently into racemic phosphanucleoside via nucleobase construction. [Copyright &y& Elsevier]

Abstract: Epimeric 5′-(RS) dialkyl 3′-deoxy-3′,4′-didehydro-5′-C-phosphonates were prepared by nucleophilic addition of various dialkyl phosphites to 3′-deoxy-3′,4′-didehydronucleoside-5′-aldehydes. Whereas direct NMR configuration assignment for the C5′ atom bearing the phosphoryl and hydroxy groups using the J (P,H4′) and J (H5′,H4′) coupling constants is impossible due to the absence of the H4′ atom, successful separation, crystallisation and X-ray crystallographic analysis of a pair of epimeric 5′-C-phosphonates, followed by correlation with a series of NMR parameters, led to efficacious configuration assignment of individual epimers in the mixtures. [Copyright &y& Elsevier]

Abstract: trans-4-Hydroxy-l-proline has been used as a starting material for the synthesis of prolinol-based nucleotide analogues with an N-phosphonomethyl moiety attached to the prolinol ring nitrogen atom. The synthetic methodology based on the inversion of configuration at both 1- and 4-position led to all diastereoisomeric O-protected 4-mesyloxyprolinol-N-phosphonates. Alkylation of nucleobases using the synthons in the l-series afforded the nucleotide analogues corresponding to α-l- and β-l-nucleotide. The NMR-based conformational study of these compounds in aqueous solution performed at two different pH values, showing either N-fully protonated or deprotonated forms, revealed the occurrence of the same mostly populated conformer in both cases. All final l-prolinol-based nucleoside phosphonic acids were tested for cytotoxic and antiviral properties, but no significant activity was found. [Copyright &y& Elsevier]

Abstract: The work deals with the synthesis of hydroxypyrrolidine analogs of nucleosides. Starting from the optically pure l- or d-tartaric acid, we improved the synthesis of enantiomeric trans-3,4-dihydroxypyrrolidines and elaborated a procedure for the synthesis of all possible diastereoisomers of 3-hydroxy-4-pyrrolidinyl derivatives of both purine and pyrimidine nucleobases. The prepared compounds were tested for cytostatic and antiviral properties but no significant activity was found. [Copyright &y& Elsevier]

Abstract: We found that various dialkyl phosphites, dialkyl trimethylsilyl phosphites, and tris-trimethylsilyl phosphite reacted smoothly with nucleoside 5′-aldehydes to afford epimeric nucleoside 5′-C-phosphonates in high yields. A number of these compounds in both the 2′-deoxyribo and ribo series were prepared. In the case of 2′-deoxythymidine-5′-aldehyde, a thorough study was made on the influence of the 3′-hydroxyl protecting group, type of phosphite, base, and solvent, on the yield and epimeric ratio of the resulting 5′-hydroxyphosphonates. Partial stereoselectivity in favour of either R or S epimers was observed. An attempt to transform the α-hydroxyl of the phosphonate moiety into a halo or azido moiety was not successful. Only intramolecular substitution reaction of the mesyloxy group for an alkoxy residue of the 2-hydroxyethyl ester took place in a low yield. [Copyright &y& Elsevier]

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. [Display omitted] [ABSTRACT FROM AUTHOR]