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Otto Dahl - One of the best experts on this subject based on the ideXlab platform.
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synthesis of oligodeoxynucleoside phosphoro monothioates and Phosphorodithioates by a phosphotriester method
Nucleosides Nucleotides & Nucleic Acids, 1997Co-Authors: Jan Kehler, Ask Puschl, Otto DahlAbstract:Abstract A phosphotriester method for the synthesis of dithymidine phosphoromonothoates and Phosphorodithioates with new S-protecting groups has been investigated. Four of the S-protecting groups possesed catalytic activity, however side reactions occurred during deprotection. The best S-protecting group was 4-chloro-2-nitlobenzyl which could be removed with a minimum of side reactions (0.3 %). The coupling reagent PyFNOP (14) gave protected dithymidine phosphoromonothioate in 96 % yield after 15 min coupling. Furthermore PyFNOP chemoselectively activates oxygen in nucleoside phosphorodithioate monomers 9 and can be used for the synthesis of oligodeoxynucleoside Phosphorodithioates with mixed base sequences.
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solid phase synthesis of oligodeoxynucleoside Phosphorodithioates by a phosphotriester method using a chemoselective coupling reagent
Tetrahedron Letters, 1996Co-Authors: Jan Kehler, Ask Puschl, Otto DahlAbstract:Abstract A phosphotriester method has been developed for solid phase synthesis of oligodeoxynucleoside Phosphorodithioates. Couplings are performed by chemoselective oxygen activation of protected nucleoside dithiophosphate anions 1, 7, 8, 9 with 4-nitro-6-trifluoromethylbenzotriazol-1-yl-oxy-tris(pyrrolidine)-phosphonium hexafluorophosphate (PyFNOP). Under optimised conditions coupling yields are above 95% for 10 – 20 min couplings, and the products after deblocking are free from phosphorothioate contaminations (detection limit 0.5%).
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NMR Investigations of Duplex Stability of Phosphorothioate and Phosphorodithioate DNA Analogues Modified in Both Strands
Nucleic Acids Research, 1996Co-Authors: Jerzy W. Jaroszewski, Vicki Clausen, Jack S. Cohen, Otto DahlAbstract:Duplex formation from the self-complementary 12mer d(CGCGAATTCGCG) (Dickerson dodecamer) in which all phosphodiester linkages were replaced by phosphorothioate or phosphorodithioate linkages was studied using variable-temperature 1H and 31P NMR spectroscopy. Melting temperatures of the dodecamer, measured spectrophotometrically, showed significant decrease upon sulfur substitution (Tm 49 degrees C for the phosphorothioate and 21 degrees C for the phosphorodithioate, compared with 68 degrees C for the unmodified oligomer, in 1 M salt). Hyperchromicity observed upon melting of the dithioate was surprisingly low. NOESY spectra of the monothioate showed a cross-peak pattern characteristic for a right-handed duplex. Imino proton resonances of the duplex, shown by the mono- and the dithioate, were similar to those of the parent compound. In spite of monophasic melting curves, temperature dependence of the imino proton resonances and phosphorus resonances of the phosphorodithioate indicated heterogeneity with respect to base-pairing, compatible with the presence of a hairpin loop. Relaxation times (T1) of the imino protons in the phosphorothioate, determined by the saturation recovery method, were considerably shorter than in the unmodified oligomer. Base-pair lifetimes in the unmodified Dickerson dodecamer, determined by catalyst-dependent changes in relaxation rates of imino protons, were in the range of 2-30 ms at 20 degrees C. Strongly reduced base-pair lifetimes were found in the phosphorothioate analogue.
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new solid phase synthesis of oligodeoxythymidine Phosphorodithioates by a modified hobt method
Tetrahedron Letters, 1995Co-Authors: Anne B Eldrup, Jan Kehler, Jakob Felding, Otto DahlAbstract:Two new dithiophosphorylating reagents 2a,b have been prepared and shown to give nucleoside monomers 3a,b with reactivities suitable for solid phase synthesis. An octamer and a nonamer deoxythymidine phosphorodithioate were prepared on a TentaGel support with good coupling efficiencies. The products after deblocking are free from phosphorothioate contaminations (detection limit 0.5%).
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preparation of nucleoside phosphorothioates Phosphorodithioates and related compounds
Sulfur Reports, 1991Co-Authors: Otto DahlAbstract:Abstract This review describes synthetic pathways to mono-, di- and oligonucleotides modified in the phosphate group(s) by substitution of one or several oxygen atoms with sulfur. The known sulfur-modified phosphate groups are nucleoside 3′- and 5′-O-phosphorothioates, nucleoside thiodi- and triphosphates, nucleoside cyclic phosphorothioates, di- and oligonucleoside O,O-phosphorothioates, nucleoside 3′-S-phosphorothioates, nucleoside and oligonucleoside 5′-S-phosphorothioates, nucleoside O-Phosphorodithioates, di- and oligonucleoside O,O-Phosphorodithioates, di- and oligonucleoside O,S-Phosphorodithioates, thiophosphortriesters, thiophosphoramidates, and methylphosphonothioates.
Marvin H Caruthers - One of the best experts on this subject based on the ideXlab platform.
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Hammerhead cleavage of the phosphorodithioate linkage.
Biochemistry, 2000Co-Authors: Wesley B. Derrick, Marvin H Caruthers, Charles H. Greef, Olke C. UhlenbeckAbstract:Under standard reaction conditions, a hammerhead ribozyme with a phosphorodithioate linkage at the cleavage site cleaved to the expected products with a rate about 500-fold slower than the corresponding phosphodiester linkage. When the greater stability of the dithioate linkage to nonenzymatic nucleophilic attack is taken into account, the hammerhead is remarkably effective at cleaving the dithioate linkage considering that the RP-phosphoromonothioate linkage is virtually inactive. On the basis of experiments determining the Mg2+ concentration dependence of the cleavage rate and the stimulation of cleavage by thiophilic Cd2+ ion, the lesser catalytic rate enhancement of the dithioate linkage is primarily due to the loss of a single Mg2+ ion bound near the cleavage site. These results are qualitatively similar to, but quantitatively different from, similar experiments examining the hammerhead cleavage properties of the RP-phosphoromonothioate linkage. The dithioate linkage thus promises to be a valuable al...
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Synthesis of phosphorodithioate DNA by the H-phosphonothioate method
Tetrahedron, 1999Co-Authors: Peter H Seeberger, Marvin H Caruthers, Danute Bankaitis-davis, Graham BeatonAbstract:Abstract A novel method for the efficientsynthesis phosphorodithioate DNA using H-phosphonothioate synthons is described. The 5′-DMT-nucleoside H-phosphonothioate monomers were prepared in two high yielding steps from commercially available phosphoramidites. This strategy for the synthesis of H-phosphonothioate monomers proved versatile and allowed for the synthesis of cholesterol H-phosphonothioate synthons. Synthetic protocols for the assembly of phosphorodithioate DNA using an automated synthesizer were developed. The H-phosphonothioate solid-phase synthesis method facilitates the preparation of oligonucleotide conjugates, as demonstrated by the example of attachment of 5′-cholesterol oligonucleotides.
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Biochemical and physicochemical properties of phosphorodithioate DNA.
Biochemistry, 1996Co-Authors: Lendell L. Cummins, Graham Beaton, William S. Marshall, Darla Graff, Marvin H CaruthersAbstract:The biochemical and physicochemical properties of DNA oligomers containing phosphorodithioate linkages in various configurations were evaluated. Duplex stability studies, which were carried out by thermal denaturation analysis with complementary unmodified DNA, indicated a highly cooperative process similar to completely unmodified duplexes. Oligomers containing phosphorodithioate linkages were found to have reduced melting temperatures relative to unmodified duplexes, with the degree of Tm depression paralleling the percent phosphorodithioate composition of the oligomer. Relative to activation of RNase H, DNA oligomers containing up to 50% phosphorodithioate linkages were able to direct RNase H degradation with the same efficiency as unmodified DNA while those containing from 50 to 100% acted with somewhat reduced efficiency. At limiting concentrations, an oligomer containing alternating phosphorodithioate and phosphate linkages was able to direct RNase H degradation of the target RNA in an extended incu...
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Synthesis of Phosphorodithioate DNA via Sulfur-Linked, Base-Labile Protecting Groups1
Journal of Organic Chemistry, 1996Co-Authors: William T. Wiesler, Marvin H CaruthersAbstract:Phosphorodithioate DNA, a new and potentially useful DNA analog with a deoxynucleoside-OPS2O-deoxynucleoside internucleotide linkage, was synthesized from deoxynucleoside 3‘-phosphorothioamidites having a variety of thioesters and thiocarbonates as base-labile phosphorus protecting groups. The major challenge in the synthesis of this DNA analog was to derive a reaction pathway whereby activation of deoxynucleoside 3‘-phosphorothioamidites occurred rapidly and in high yield under conditions that minimize Arbuzov rearrangements, exchange reactions, unwanted oxidation to phosphorothioates, and several other side reactions. Of the various phosphorus protecting groups examined for this purpose, a thorough evaluation of these parameters led to the conclusion that β-(benzoylmercapto)ethyl was preferred. Synthesis of phosphorodithioate DNA began by preparing deoxynucleoside 3‘-phosphorothioamidites from the appropriately protected deoxynucleoside, tris(pyrrolidino)phosphine, and ethanedithiol monobenzoate via a o...
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oxidative formation of Phosphorodithioates via h phosphonodithioates
Tetrahedron Letters, 1995Co-Authors: Peter H Seeberger, Marvin H CaruthersAbstract:Abstract H-Phosphonodithioate esters can be linked to a second alcohol via an oxidative coupling procedure to generate a phosphorodithioate diester. Nucleoside-cholesterol and nucleoside-amino acid Phosphorodithioates were synthesized via this route.
Maria Michalska - One of the best experts on this subject based on the ideXlab platform.
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a novel and practical synthesis of s 1 and 2 halogenoalkyl sugars by reaction of carbohydrate s o o dialkyl Phosphorodithioates and monothioates with fluoride anion
Tetrahedron Letters, 2004Co-Authors: Halszka Bielawska, Maria MichalskaAbstract:Abstract A useful synthesis has been developed of S -(1- and 2-halogenoalkyl)sugars in high yield and purity. Readily available sugar S -( O , O -dialkyl)Phosphorodithioates undergo S–P bond rupture on reaction with fluoride ions to yield the corresponding sugar thiolates, which further react in situ with dichloromethane or 1,2-dihalogenoalkanes in the reaction medium. In this reaction, the halogenoalkanes play the role of both reactants and solvents.
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highly efficient synthesis of Phosphorodithioates derived from 3 thiothymidine by anhydro ring opening of 2 3 anhydro 5 o tritylthymidine with o o disubstituted phosphorodithioic acids
Chemical Communications, 1998Co-Authors: Wojciech Da Bkowski, Izabela Tworowska, Maria MichalskaAbstract:Thymidine 3′-S-phosphorodithioate 4 and dithymidine-3′-S-phosphorodithioate 7 derived from 3′-thiothymidine are synthesized in excellent yield under mild conditions by the nucleophilic ring opening of 2,3′-anhydrothymidine with phosphorodithioic acids.
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Highly efficient synthesis of Phosphorodithioates derived from 3′-thiothymidine by anhydro-ring opening of 2,3′-anhydro-5′-O-tritylthymidine with O,O-disubstituted phosphorodithioic acids
Chemical Communications, 1998Co-Authors: Wojciech Da Bkowski, Izabela Tworowska, Maria MichalskaAbstract:Thymidine 3′-S-phosphorodithioate 4 and dithymidine-3′-S-phosphorodithioate 7 derived from 3′-thiothymidine are synthesized in excellent yield under mild conditions by the nucleophilic ring opening of 2,3′-anhydrothymidine with phosphorodithioic acids.
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efficient synthesis of 2 deoxyglycosyl 1 o acyl esters via 2 deoxyglycosyl Phosphorodithioates as glycosyl donors
Synthesis, 1994Co-Authors: Joanna Borowiecka, Maria MichalskaAbstract:An efficient glycosylation of carboxylic acids 2a-p has been developed employing 2-deoxyglycosyl Phosphorodithioates 1a-h as glycosyl donors and Ag + salts as activators. In the case of aliphatic acids the method is highly β-stereoselective. Stereoselectivity of glycosylation of aromatic acids depends on their structure. The α/β ratio is temperature dependent. Hydroxy groups in α-hydroxycarboxylic acids are not affected by glycosylation under the reaction conditions used
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a highly stereoselective synthesis of n alkyl 2 deoxy β d arabino hexopyranosyl amines via 2 deoxyglycosyl Phosphorodithioates as glycosyl donors
Journal of Carbohydrate Chemistry, 1993Co-Authors: Maria Michalska, Wieslawa Kudelska, January Pluskowski, Mariolo Nowinska, Anna JuszczakAbstract:Abstract This work demonstrates a new application of 2-deoxy-α-D-glycosyl Phosphorodithioates 1 as glycosyl donors in the synthesis of N-alkyl-(2-deoxy-D-arabino-hexopyranosyl)amines 3. The reaction of 1 with amines 2 proceeds with high β-stereoselectivity, at ambient temperature, in almost quantitative yield.
Roger A G Marshall - One of the best experts on this subject based on the ideXlab platform.
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the thermal degradation of zinc o o dialkyl Phosphorodithioates and related compounds in petroleum media part 1 zinc o o diisobutyl phosphorodithioate
Journal of Chemical Technology & Biotechnology, 2007Co-Authors: Raymond J Ellis, Peter J Lake, Roger A G MarshallAbstract:The thermal decomposition of zinc O,O-dialkyl Phosphorodithioates is acknowledged to play a significant part in their activity as multipurpose lubricating oil additives. Therefore, the isobutyl derivative in pentadecane solution has been degraded in a novel apparatus under a nitrogen atmosphere. The principal volatile products were found by gas-liquid chromatography and mass spectrometry to be O,O,S-triisobutyl phosphorodithioate, isobutanethiol and isobutene. In addition to these volatile products a solid (insoluble in organic solvents) was formed. This contained virtually all the zinc in the original reactant and had a zinc: phosphorus ratio of 2:3. It also contained carbon, hydrogen, sulphur and oxygen but the proportions of the latter two elements were unreliable. Variation of the period of heating, the temperature from 176 to 240°C and the concentration of the reactant from 1.4 to 7.0 × 10−2M affected the relative proportion but not the nature of the products formed. An equation involving the reaction of two molecules of the reactant has been written but kinetic data is required in order to establish a mechanism.
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The thermal degradation of zinc O,O‐dialkyl Phosphorodithioates and related compounds in petroleum media. Part 1. Zinc O,O‐diisobutyl phosphorodithioate
Journal of Chemical Technology & Biotechnology, 2007Co-Authors: Raymond J Ellis, Peter J Lake, Roger A G MarshallAbstract:The thermal decomposition of zinc O,O-dialkyl Phosphorodithioates is acknowledged to play a significant part in their activity as multipurpose lubricating oil additives. Therefore, the isobutyl derivative in pentadecane solution has been degraded in a novel apparatus under a nitrogen atmosphere. The principal volatile products were found by gas-liquid chromatography and mass spectrometry to be O,O,S-triisobutyl phosphorodithioate, isobutanethiol and isobutene. In addition to these volatile products a solid (insoluble in organic solvents) was formed. This contained virtually all the zinc in the original reactant and had a zinc: phosphorus ratio of 2:3. It also contained carbon, hydrogen, sulphur and oxygen but the proportions of the latter two elements were unreliable. Variation of the period of heating, the temperature from 176 to 240°C and the concentration of the reactant from 1.4 to 7.0 × 10−2M affected the relative proportion but not the nature of the products formed. An equation involving the reaction of two molecules of the reactant has been written but kinetic data is required in order to establish a mechanism.
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the thermal degradation of zinc o o dialkyl Phosphorodithioates and related compounds in petroleum media part ii kinetic studies of zinc o o diisobutyl phosphorodithioate
Journal of Chemical Technology & Biotechnology, 2007Co-Authors: Peter J Lake, Roger A G MarshallAbstract:The period of usefulness and the mode of action of zinc O, O-dialkyl Phosphorodithioates as multipurpose oil additives are affected by their thermal decomposition. Therefore, solutions of the diisobutyl derivative in pentadecane solution were heated under a nitrogen atmosphere at temperatures from 176 to 228°C in an all-glass apparatus which enabled periodic removal of samples. The rate of loss of zinc from solution and the rates of formation of the products O, O, S-triisobutyl phosphorodithioate, isobutanethiol and isobutene were then determined by atomic absorption spectroscopy and gas chromatography. It was found that all the zinc O, O-diisobutyl phosphorodithioate had reacted in a time varying from 225 to 324 min depending upon its concentration at 215°C, but that O, O, S-triisobutyl phosphorodithioate and isobutanethiol underwent further reaction. Induction periods varying from 33 to 120 min were observed for loss of zinc from solution and the formation of all the products; these were ascribed to the formation of an elusive intermediate which reacted at a rate comparable to that at which it was formed.
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The thermal degradation of zinc O, O‐dialkyl Phosphorodithioates and related compounds in petroleum media. Part II. Kinetic studies of zinc O, O‐diisobutyl phosphorodithioate
Journal of Chemical Technology & Biotechnology, 2007Co-Authors: Peter J Lake, Roger A G MarshallAbstract:The period of usefulness and the mode of action of zinc O, O-dialkyl Phosphorodithioates as multipurpose oil additives are affected by their thermal decomposition. Therefore, solutions of the diisobutyl derivative in pentadecane solution were heated under a nitrogen atmosphere at temperatures from 176 to 228°C in an all-glass apparatus which enabled periodic removal of samples. The rate of loss of zinc from solution and the rates of formation of the products O, O, S-triisobutyl phosphorodithioate, isobutanethiol and isobutene were then determined by atomic absorption spectroscopy and gas chromatography. It was found that all the zinc O, O-diisobutyl phosphorodithioate had reacted in a time varying from 225 to 324 min depending upon its concentration at 215°C, but that O, O, S-triisobutyl phosphorodithioate and isobutanethiol underwent further reaction. Induction periods varying from 33 to 120 min were observed for loss of zinc from solution and the formation of all the products; these were ascribed to the formation of an elusive intermediate which reacted at a rate comparable to that at which it was formed.
John Nielsen - One of the best experts on this subject based on the ideXlab platform.
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synthesis of deoxydinucleoside Phosphorodithioates
Journal of the American Chemical Society, 1991Co-Authors: Wolfgang K D Brill, John Nielsen, Marvin H CaruthersAbstract:Two methods are described for synthesizing this derivative. One route begins by condensing a deoxynucleoside phosphorodiamidite with a second appropriately protected deoxynucleoside to yield a deoxydinucleoside phosphoramidite. Sulfhydrolysis with H 2 S generates the H-phosphonothioate, which upon oxidation with sulfur yields the deoxydinucleoside phosphorodithioate. Alternatively, sequential treatment of the deoxydinucleoside phosphoramidite with a mercaptan and sulfur yields the deoxydinucleoside phosphorodithioate triester. These deoxydinucleotides in protected form can then be used to introduce the dithioate internucleotide linkage into DNA. The second route for generating dithioate DNA uses deoxynucleoside phosphorothioamidites
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synthesis of oligodeoxynucleoside Phosphorodithioates by a phosphortriester method
Nucleosides Nucleotides & Nucleic Acids, 1991Co-Authors: Bjame H Dahl, John Nielsen, Kirsten Bjerghde, Otto DahlAbstract:Abstract A new method for preparation of oligodeoxynucleoside Phosphorodithioates using a phosphortriester approach is presented.
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synthesis of oligonucleotide Phosphorodithioates
Tetrahedron, 1991Co-Authors: Graham Beaton, John Nielsen, Wolfgang K D Brill, A Grandas, Marvin H CaruthersAbstract:Abstract The synthesis of DNA containing sulfur at the two nonbonding internucleotide valencies is reported. Several different routes using either tervalent or pentavalent mononucleotide synthons are described.
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Chemical synthesis of dimer ribonucleotides containing internucleotidic phosphorodithioate linkages
Tetrahedron Letters, 1990Co-Authors: Kenneth H. Petersen, John NielsenAbstract:Ribonucleosides, chlorobis(amino)phosphines and thiols react via phosphorothioamidites to form phosphorothioites. Oxidation with sulphur gives ribonucleoside phosphorodithioate triesters which after deprotection yields the phosphorodithioate ribonucleoside analogues.
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deoxynucleoside Phosphorodithioates preparation by a triester method
Tetrahedron Letters, 1990Co-Authors: Bjarne H Dahl, John Nielsen, Otto DahlAbstract:Abstract A series of active esters of dithiophosphoric acid (3) have been prepared and their properties as potential precursors for dideoxynucleoside Phosphorodithioates evaluated.