PubMed Health⌕ Search

Biomedical subjects

J Stawiński

Publications and source records attributed to J Stawiński.

15 recordsLinked to original sources
PubMed2001

Interaction of thymidylate synthase with the 5'-thiophosphates, 5'-dithiophosphates, 5'-H-phosphonates and 5'-S-thiosulfates of 2'-deoxyuridine, thymidine and 5-fluoro-2'-deoxyuridine.

New analogs of dUMP, dTMP and 5-fluoro-dUMP, including the corresponding 5'-thiophosphates (dUMPS, dTMPS and FdUMPS), 5'-dithiophosphates (dUMPS2, dTMPS2 and FdUMPS2), 5'-H-phosphonates (dUMP-H, dTMP-H and FdUMP-H) and 5'-S-thiosulfates (dUSSO3, dTSSO3 and FdUSSO3), have been synthesized and their interactions studied with highly purified mammalian thymidylate synthase. dUMPS and dUMPS2 proved to be good substrates, and dTMPS and dTMPS2 classic competitive inhibitors, only slightly weaker than dTMP. Their 5-fluoro congeners behaved as potent, slow-binding inhibitors. By contrast, the corresponding 5'-H-phosphonates and 5'-S-thiosulfates displayed weak activities, only FdUMP-H and FdUSSO3 exhibiting significant interactions with the enzyme, as weak competitive slow-binding inhibitors versus dUMR The pH-dependence of enzyme time-independent inhibition by FdUMP and FdUMPS was found to correlate with the difference in pKa values of the phosphate and thiophosphate groups, the profile of FdUMPS being shifted (approximately 1 pH unit) toward lower pH values, so that binding of dUMP and its analogs is limited by the phosphate secondary hydroxyl ionization. Hence, together with the effects of 5'-H-phosphonate and 5'-S-thiosulfate substituents, the much weaker interactions of the nucleotide analogs (3-5 orders of magnitude lower than for the parent 5'-phosphates) with the enzyme is further evidence that the enzyme's active center prefers the dianionic phosphate group for optimum binding.

Enzyme Activation↗
PubMed2001

Nucleoside phosphate analogues of biological interest, and their synthesis via aryl nucleoside H-phosphonates as intermediates.

This review presents a brief account of the chemistry and mechanistic aspects of aryl H-phosphonates, and selected applications of this class of compounds as intermediates in the synthesis of a wide range of biologically important analogues of nucleoside phosphates, and oligonucleotides, in which the phosphate moieties are replaced by other structurally related groups. The aryl nucleoside H-phosphonates, compounds of controlled reactivity, have proven to be more versatile and superior to various mixed anhydrides as synthetic intermediates, particularly for preparation of nucleotide analogues bearing P-N or P-S bonds in various configurational arrangements at the phosphate moiety.

Catalysis↗
PubMed2000

Aryl H-phosphonates. 12. Synthetic and (31)P NMR studies on the preparation of nucleoside H-phosphonothioate and nucleoside H-phosphonodithioate monoesters.

Transformation of nucleoside H-phosphonate monoesters into the corresponding H-phosphonothioate and H-phosphonodithioate derivatives and possible side-reactions that may accompany this process were studied using (31)P NMR spectroscopy. These provided new insight into a possible mechanism involved in this transformation and constituted the basis for development of efficient methods for the preparation of nucleoside H-phosphonothioate and nucleoside H-phosphonodithioate monoesters using readily available H-phosphonate monoesters as starting materials.

Esters↗
PubMed1999

Synthesis and anti-retroviral activity of O,O'-bis(3'-azido-2',3'-dideoxythymidin-5'-yl) phosphoramidate derivatives.

A simple and efficient protocol for the preparation of various symmetrical dinucleoside phosphoramidates derived from AZT, is presented. It consists of the phosphonylation of AZT with phosphonic acid in the presence of DCC to produce the symmetrical H-phosphonate diester, followed by its oxidative conversion to various phosphoramidate analogues. The synthesized compounds were evaluated for their anti-HIV activity in different cell cultures.

Amides↗
PubMed1998

Some aspects of oligoribonucleotides synthesis via the H-phosphonate approach.

This review gives a short account of selected aspects of oligoribonucleotide synthesis via the H-phosphonate method. It includes: (i) recent methods for the preparation of suitably protected ribonucleoside 3'-H-phosphonates (the phosphonylation step), (ii) some chemical and stereochemical features of the formation of H-phosphonate internucleosidic linkages, and (iii) stereoselective synthesis of oligoribonucleoside phosphorothioates using chemo-enzymatic approach.

Nucleic Acids↗
PubMed1998

Hydration of C-H groups in natural dithymidine nucleotide and its methylphosphonate analogues.

In this paper we report our preliminary studies on the hydration pattern of selected C-H groups in natural thymidyl(3'-5)thymidine and its Rp and Sp-methylphosphonate analogues using Molecular Dynamic simulations in aqueous solutions. The methyl groups attached to the phosphorus center (P-Me) in methylphosphonate analogues are hydrated by water molecules as efficiently as the hydrophilic P=O group in the natural dithymidine nucleotide and better than the neutral P=O functions in these compounds, although the nature of the hydration is different. The C5-Me centers of the 3'-yl units seem to be better hydrated in the methylphosphonate analogues than in the natural dithymidine phosphate and than other centers of the thymine bases in methylphosphonate analogues. Due to chirality of the phosphorus center, the C5-Me group of the 5'-yl unit in the Sp diastereomer coordinates more water than that in the Rp diastereomer. The C6-H group in the 5'-yl unit of the Sp diastereomer exhibits a specific interaction with water.

Carbon↗
PubMed1997

FTIR study on nucleotide analogues. 1. Spectral characterization of dinucleoside methylphosphonates and dinucleoside 5'-methylenephosphonates in solution and in solid phase.

Some conformational feature of dithymidine nucleotides containing natural 3'-->5' phosphodiester, methylphosphonate, or 5'-methylenephosphonate internucleotidic linkages were probed in solution and in solid phase using FTIR spectroscopy. A high similarity of the IR spectra in the region of 1800-1250 cm-1 indicates that all the investigated compounds have similar glycosidic torsion angels and the preferred conformation of the deoxyribose rings. However, small but significant differences between the Rp and Sp diastereomers of methylphosphonate analogue 5 may suggest that the association or the hydration mode of these compounds may vary.

DNA Methylation↗
PubMed1980

The case of sulfonation in the chemical synthesis of oligonucleotides.

The sulfonation of nucleosidic component, a side reaction during phosphotriester bond formation, as a function of the reactivity of the condensing agents and the kind of substituents in the starting phosphodiester is discussed. It was found that in the coupling reaction of nucleoside alkyl phosphodiesters, the degree of sulfonation of the nucleosidic component was very high; while under the same conditions when the aryl group was present in the corresponding phosphodiester, this side reaction practically did not occur.

Arylsulfonates↗
PubMed1980

Further studies on oligoribonucleotide synthesis.

Recent results concerning the synthesis of oligoribonucleotides via the phosphotriester method, such as functionalization of ribonucleosides, new phosphorylating agents, 5'-O-sulfonylation and chromatography on Sephadex LH-20 for monitoring the removal of internucleotide phosphotriester groups, are presented. To show that efficiency of a new approach to the synthesis of oligoribonucleotides the pentamer /Up/4U was obtained.

Esters↗
PubMed1978

The chemical synthesis of the anticodon loop of an eukaryotic initiator tRNA containing the hypermodified nucleoside N6-/N-threonylcarbonyl/-adenosine/t6A/1.

In this work, the first example of chemical synthesis of oligoribonucleotide containing the hypermodified nucleoside N6-/N-threonylcarbonyl/-adenosine /t6A/ is presented. Synthesis of the heptamer C-C-C-A-U-t6A-A IX, the sequence of which is related to the anticodon loop of the initiator tRNA from yellow lupine, was achieved by: /i/ phosphotriester block synthesis of suitably protected heptamer VI containing an adenosine unit with a free exo-NH2 group, /ii/ highly effective "one-flask" procedure for the transformation of the free exo-NH2 group of adenosine unit of heptamer VI into a N,N'-disubstituted urea system of t6A of heptamer VII /hypermodification/, and /iii/ final deprotection of VIII /32% total yield/ with the use of a new approach for simultaneous hydrogenolysis /PdO-hydrogen-pyridine/ of the p-nitrobenzyl group and 2,2,2-trichloroethyl groups from carboxyl function of t6A and internucleotide phosphates respectively.

Adenosine↗
PubMed1977

Nucleoside 3'-phosphotriesters as key intermediates for the oligoribonucleotide synthesis. IV. New method for removal of 2,2,2-trichloroethyl group and 31P NMR as a new tool for analysis of deblocking of internucleotide phosphate protecting groups.

Zinc/acetylacetone/pyridine treatment has been designed as a very efficient method for removal of 2,2,2,-trichloroethyl group from phosphoesters. Internucleotide and terminal 2,2,2-trichloroethylphosphotriesters were transformed to corresponding diesters quantitatively. Much less reactive 2,2,2-trichloroethylphosphodiesters produced monoesters with ca. 90% yield. 31P NMR spectroscopy has been proposed as a new tool for analysis of removal of internucleotide phosphate protecting groups-a crucial step in oligonucleotides synthesis via phosphotriester approach.

Chromatography, Thin Layer↗
PubMedDate not supplied

Studies on reactions of nucleoside H-phosphonates with bifunctional reagents. Part VI. Reaction with diols.

Reactions of nucleoside H-phosphonates with various diols using different types of condensing agents have been studied. Depending on the coupling procedure and the length of a polymethylene chain of the diol, acyclic H-phosphonate diesters or cyclic phosphite triesters were formed. The course of oxidation with iodine to produce cyclic nucleoside alkyl phosphotriesters or hydroxyalkyl nucleoside phosphodiesters can be controlled by the amount of water present in the reaction medium.

Indicators and Reagents↗