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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]

Abstract: A series of conformationally constrained uridine-based nucleoside phosphonic acids containing annealed 1,3-dioxolane and 1,4-dioxane rings and their “open-structure” isosteres were synthesized and evaluated as potential multisubstrate-like inhibitors of the human recombinant thymidine phosphorylase (TP, EC 2.4.2.4) and TP obtained from peripheral blood mononuclear cells (PBMC). From a large set of tested nucleoside phosphonic acids, several potent compounds were identified that exhibited K i values in the range of 0.048–1 μM. The inhibition potency of the studied compounds strongly depended on the degree of conformational flexibility of the phosphonate moiety, the stereochemical arrangement of the sugar-phosphonate component, and the substituent at position 5 of the pyrimidine nucleobase. [Copyright &y& Elsevier]

A complete series of pyrrolidine nucleotides, (3R)- and (3S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acids and (3S,4R)-, (3R,4S)-, (3S,4S)-, and (3R,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acids, were synthesized and evaluated as potentialinhibitors of purine nucleoside phosphorylase (PNP) isolated fromperipheral blood mononuclear cells (PBMCs) and cell lines of myeloidand lymphoid origin. Two compounds, (S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acid (2a) and (3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acid (6a), were recognizedas nanomolar competitive inhibitors of PNP isolated from cell lineswith Kivalues within the ranges of 16–100and 10–24 nM, respectively. The low MESGKiand PiKivalues of both compounds for PNP isolated from PBMCs suggest thatthese compounds could be bisubstrate inhibitors that occupy both thephosphate and nucleoside binding sites of the enzyme. [ABSTRACT FROM AUTHOR]

Abstract: 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 IC50 values below 1μM were selected. Out of them, four compounds strongly inhibited the enzyme with IC50 values lying in a range of 11–45nM. These most potent compounds might be bi-substrate analogues. [Copyright &y& Elsevier]

Abstract: N-Phosphonoalkyl-trans-3,4-dihydroxypyrrolidine derivatives were synthesized and exploited as synthons for the preparation of hydroxypyrrolidine nucleoside phosphonic acids, the 3′-deoxynucleoside 5′-phosphate analogues. Simultaneously, an alternative route, the N-phosphoalkylation of the preformed pyrrolidine nucleosides employing Mannich- and Michael-type reactions, was investigated to obtain desired nucleotide analogues. In contrast to the latter approach, the former resulted in the formation of two diastereoisomers very likely due to the existence of two possible SN2 transition states during a nucleophilic displacement. The stereochemistry of the prepared nucleotide analogues was studied by NMR spectroscopy. [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: An electrophile-promoted addition of dialkyl-hydroxymethylphosphonate to the protected 4′,5′-didehydronucleosides resulted in an epimeric mixture of 4′-dialkylphosphonomethoxy derivatives of 2′,5′-dideoxynucleosides, novel analogues of 2′-deoxynucleoside 5′-monophosphates. Several types of electrophiles (pyridinium tosylate, NIS, NBS, MCPBA and others) were evaluated in addition reactions with 4′,5′-didehydrothymidine. Out of them, pyridinium tosylate was found to have a practical usefulness in these transformations. Its use has led to the preparation of a series of 4′-phosphonomethoxy derivatives of common 2′-deoxynucleosides. On biological screening, these free phosphonic acids exerted no significant cytostatic or antiviral activity. [Copyright &y& Elsevier]

Abstract: We report here an oxidative cleavage of (5R)- and (5S)-ribofuranosyl-5-C-phosphonate derivatives with periodate anion under both strong acidic and neutral conditions. In both cases, only (5R)-configured compound underwent the expected oxidation reaction and afforded the desired (4R)-erythrofuranosylphosphonate, whereas the second epimer, (5S)-ribofuranosyl-5-C-phosphonate did not provide the corresponding (4S)-erythrofuranosylphosphonate derivative. This different behavior of epimers toward oxidative cleavage is an important phenomenon. The obtained (4R)-erythrofuranosylphosphonate was used for the preparation of phosphonate mimic of adenosine 5′-phosphate via classical nucleosidation reaction. Condensation of the protected shortened AMP analogue with adenosine derivatives, however, provided only the 2′,5′-linked ApA analogue. Study on hybridization of the modified 2′-5′ ApA with polyU revealed its ability to form stable triplex-like complex, similar to natural 2′-5′ r(ApA) and 3′-5′ r(ApA). NMR spectroscopy study showed that the erythrofuranose part of the phosphonate nucleotide unit of modified 2′-5′ ApA was predominantly in the C2′-endo conformation, which is characteristic for B-DNA. [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]