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Modified internucleotide linkage featuring the C3'-O-P-CH(2)-O-C4'' phosphonate grouping as an isosteric alternative to the phosphodiester C3'-O-P-O-CH(2)-C4'' bond was studied in order to learn more on its stereochemical arrangement, which we showed earlier to be of prime importance for the properties of the respective oligonucleotide analogues. Two approaches were pursued: First, the attempt to prepare the model dinucleoside phosphonate with (13)C-labeled CH(2) group present in the modified internucleotide linkage that would allow for a more detailed evaluation of the linkage conformation by NMR spectroscopy. Second, the use of ab initio calculations along with molecular dynamics (MD) simulations in order to observe the most populated conformations and specify main structural elements governing the conformational preferences. To deal with the former aim, a novel synthesis of key labeled reagent (CH(3)O)(2)P(O)(13)CH(2)OH for dimer preparation had to be elaborated using aqueous (13)C-formaldehyde. The results from both approaches were compared and found consistent., ((c) 2009 Wiley Periodicals, Inc.)

Phosphonate analogs of mono- and oligonucleotides with the P-C-O-C5' moiety have interesting biochemical and biophysical properties. A series of novel compounds, S-methylphosphonate-based nucleotides, with the P-C-S-C5' linkage was prepared as monomers for solid phase synthesis of modified oligonucleotides. Replacement of the 5'-oxygen atom with more nucleophilic, bulky, and lipophilic sulfur atom may influence the physicochemical and biological properties of nucleoside 5'-S-methylphosphonates and chimeric oligonucleotides as well.

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

A novel alpha- and beta-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.

The recently described epimeric nucleosidyl-5'-C-phosphonates (alpha-hydroxyphosphonates) represent novel nucleotide analogues that can be incorporated into chimeric oligonucleotides by the phosphotriester condensation method. In order to prepare suitable protected monomer(s) we have studied condensation reaction between protected 2'-deoxythymidine and 2'-deoxythymidinyl-5'-C-phosphonate, both as model compounds, in dependence on the nature of the 5'-hydroxyl protecting group. We have found that the O-acetyl group is unstable in the presence of TPSCl or MSNT used as condensing agents for activation of the phosphorus moiety. This instability negatively influences the scope of the condensation process. On the other hand, introduction of the O-methoxycarbonyl group gave excellent results. The O-methoxycarbonyl group does not participate in the condensation process, and its quantitative introduction into the nucleotide analo gues is accomplished using a novel acylating agent, methoxycarbonyl tetrazole.

A complete series of the 2 '-5 ' and 3 '-5 ' regioisomeric types of r(ApA) and 2 '-d(ApA) analogues with the α-hydroxy-phosphonate C3 '-O-P-CH(OH)-C4 '' internucleotide linkage, isopolar but non-isosteric with the phosphodiester one, were synthesized and their hybridization properties with polyU studied. Due to the chirality on the 5 '-carbon atom of the modified internucleotide linkage bearing phosphorus and hydroxy moieties, each regioisomeric type of ApA dimer is split into epimeric pairs. To examine the role of the 5 '-hydroxyl of the α-hydroxy-phosphonate moiety during hybridization, the appropriate r(ApA) analogues with 3 '(2 ')-O-P-CH2-C4 '' linkage lacking the 5 '-hydroxyl were synthesized. Nuclear magnetic resonance (NMR) spectroscopy study on the conformation of the modified sugar-phosphate backbone, along with the hybridization measurements, revealed remarkable differences in the stability of complexes with polyU, depending on the 5 '-carbon atom configuration. Potential usefulness of the α-hydroxy-phosphonate linkage in modified oligoribonucleotides is discussed. [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]

An unique set of 5′-O- and 3′-O-phosphonomethyl derivatives of four natural 2′-deoxyribonucleosides, 1-(2-deoxy-β-D-threo-pentofuranosyl)thymine, 5′-O- and 2′-O-phosphonomethyl derivatives of 1-(3-deoxy-β-D-erythro-pentofuranosyl)thymine, and 1-(3-deoxy-β-D-threo-pentofuranosyl)thymine has been synthesized as a pool of monomers for the synthesis of modified oligonucleotides. The phosphonate moiety was protected with 4-methoxy-1-oxido-2-pyridylmethyl ester group, serving also as an intramolecular catalyst in the coupling step. [ABSTRACT FROM AUTHOR]

This work deals with isopolar, phosphonate-based nucleotide analogues containing a bridging P-C bond instead of the ester P-O linkage. Specifically, starting from activated derivatives 1, 2, and 3, a simple process for preparation of mixtures of short oligomers and their analyses were elaborated. [ABSTRACT FROM AUTHOR]

Discusses a study on the hybridization of 4'-branched oligonucleotides. Preparation of 4'-Modified monomers in spite of chemical difficulties and significant decomposition of the compound during the key reaction steps; Details of the enzymatic resistance of the oligonucleotides; Measurement of the nuclear magnetic resonance spectra.

The recently described epimeric nucleosidyl-5′-C-phosphonates (α-hydroxyphosphonates) represent novel nucleotide analogues that can be incorporated into chimeric oligonucleotides by the phosphotriester condensation method. In order to prepare suitable protected monomer(s) we have studied condensation reaction between protected 2′-deoxythymidine and 2′-deoxythymidinyl-5′-C-phosphonate, both as model compounds, in dependence on the nature of the 5′-hydroxyl protecting group. We have found that the O-acetyl group is unstable in the presence of TPSCl or MSNT used as condensing agents for activation of the phosphorus moiety. This instability negatively influences the scope of the condensation process. On the other hand, introduction of the O-methoxycarbonyl group gave excellent results. The O-methoxycarbonyl group does not participate in the condensation process, and its quantitative introduction into the nucleotide analogues is accomplished using a novel acylating agent, methoxycarbonyl tetrazole. [ABSTRACT FROM AUTHOR]

A series of novel, unusual type of acyclic phosphonate-based nucleotide analogues related to well-known antivirals (PMEA and HPMPA) was synthesized using easily available synthon. These compounds, which are distinguished for the presence of phosphonomethyl acetal linkage, form a group of derivatives that contribute to the understanding of structure-activity relationship within the area of acyclic nucleotide analogues. [ABSTRACT FROM AUTHOR]

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: 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]