- Probing the binding requirements of modified nucleosides with the dna nuclease snm1a
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SNM1A is a nuclease that is implicated in DNA interstrand crosslink repair and, as such, its inhibition is of interest for overcoming resistance to chemotherapeutic crosslinking agents. However, the number and identity of the metal ion(s) in the active site of SNM1A are still unconfirmed, and only a limited number of inhibitors have been reported to date. Herein, we report the synthesis and evaluation of a family of malonate-based modified nucleosides to investigate the optimal positioning of metal-binding groups in nucleoside-derived inhibitors for SNM1A. These compounds include ester, carboxylate and hydroxamic acid malonate derivatives which were installed in the 5′-position or 3′-position of thymidine or as a linkage between two nucleosides. Evaluation as inhibitors of recombinant SNM1A showed that nine of the twelve compounds tested had an inhibitory effect at 1 mM concentration. The most potent compound contains a hydroxamic acid malonate group at the 5′-position. Overall, our studies advance the understanding of requirements for nucleoside-derived inhibitors for SNM1A and indicate that groups containing a negatively charged group in close proximity to a metal chelator, such as hydroxamic acid malonates, are promising structures in the design of inhibitors.
- Dürr, Eva-Maria,McGouran, Joanna F.
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- MODIFIED OLIGOMERIC COMPOUNDS AND USES THEREOF
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The present disclosure provides oligomeric compounds comprising a modified oligonucleotide having at least one stereo-non-standard nucleoside. An oligomeric compound comprising a modified oligonucleotide consisting of 12-30 linked nucleosides, wherein at least one nucleoside of the modified oligonucleotide is a stereo-non-standard nucleoside; and wherein the oligomeric compound is selected from among an RNAi compound, a modified CRISPR compound, and an artificial mRNA compound.
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Page/Page column 85; 189-190
(2021/02/19)
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- Synthesis and evaluation of 3′-[18F]fluorothymidine-5′-squaryl as a bioisostere of 3′-[18F]fluorothymidine-5′-monophosphate
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The squaryl moiety has emerged as an important phosphate bioisostere with reportedly greater cell permeability. It has been used in the synthesis of several therapeutic drug molecules including nucleoside and nucleotide analogues but is yet to be evaluated in the context of positron emission tomography (PET) imaging. We have designed, synthesised and evaluated 3′-[18F]fluorothymidine-5′-squaryl ([18F]SqFLT) as a bioisostere to 3′-[18F]fluorothymidine-5′-monophosphate ([18F]FLTMP) for imaging thymidylate kinase (TMPK) activity. The overall radiochemical yield (RCY) was 6.7 ± 2.5% and radiochemical purity (RCP) was >90%. Biological evaluationin vitroshowed low tracer uptake (?1) but significantly discriminated between wildtype HCT116 and CRISPR/Cas9 generated TMPK knockdown HCT116shTMPK?. Evaluation of [18F]SqFLT in HCT116 and HCT116shTMPK?xenograft mouse models showed statistically significant differences in tumour uptake, but lacked an effective tissue retention mechanism, making the radiotracer in its current form unsuitable for PET imaging of proliferation.
- Brickute,Beckley,Allott,Braga,Barnes,Thorley,Aboagye
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p. 12423 - 12433
(2021/04/07)
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- MODIFIED OLIGOMERIC COMPOUNDS AND USES THEREOF
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The present disclosure provides oligomeric compounds comprising a modified oligonucleotide having at least one stereo-non-standard nucleoside.
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Page/Page column 92
(2020/05/15)
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- Red light-controlled polymerase chain reaction
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A 23-mer DNA "caged" at its 3′-terminus with a 9-anthracenyl moiety was prepared. It can be uncaged in the presence of photosensitizer (In(pyropheophorbide-a)chloride)-containing DNAs (9-12 mers) and upon irradiation with red light. This mixture of DNAs was used to design red-light controlled polymerase chain reaction.
- Meyer,Schikora, Margot,Mokhir
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p. 13324 - 13326
(2015/08/24)
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- Radiolabeled cyclosaligenyl monophosphates of 5-iodo-2′-deoxyuridine, 5-iodo-3′-fluoro-2′,3′-dideoxyuridine, and 3′-fluorothymidine for molecular radiotherapy of cancer: Synthesis and biological evaluation
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Targeted molecular radiotherapy opens unprecedented opportunities to eradicate cancer cells with minimal irradiation of normal tissues. Described in this study are radioactive cyclosaligenyl monophosphates designed to deliver lethal doses of radiation to cancer cells. These compounds can be radiolabeled with SPECT- and PET-compatible radionuclides as well as radionuclides suitable for Auger electron therapies. This characteristic provides an avenue for the personalized and comprehensive treatment strategy that comprises diagnostic imaging to identify sites of disease, followed by the targeted molecular radiotherapy based on the imaging results. The developed radiosynthetic methods produce no-carrier-added products with high radiochemical yield and purity. The interaction of these compounds with their target, butyrylcholinesterase, depends on the stereochemistry around the P atom. IC50 values are in the nanomolar range. In vitro studies indicate that radiation doses delivered to the cell nucleus are sufficient to kill cells of several difficult to treat malignancies including glioblastoma and ovarian and colorectal cancers.
- Kortylewicz, Zbigniew P.,Kimura, Yu,Inoue, Kotaro,MacK, Elizabeth,Baranowska-Kortylewicz, Janina
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p. 2649 - 2671
(2012/06/16)
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- STABILISATION OF RADIOPHARMACEUTICAL PRECURSORS
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The invention relates to a method for improving stability of radiopharmaceutical precursors, and in particular non radiolabelled nucleoside derivatives which are used as precursors for production of radiolabelled nucleoside derivatives for use in in vivo imaging procedures such as positron emission tomography (PET). The invention further includes formulations of radiopharmaceutical precursors, and cassettes for automated synthesis apparatus comprising the same.
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- Radiologic Agents for Monitoring Alzheimer's Disease Progression and Evaluating a Response to Therapy and Processes for the Preparation of Such Agents
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Disclosed are certain cycloSalingenyl pyrimidine nucleoside monophosphates comprising positron emitters or gamma-emitting radiohalides, uses thereof for monitoring Alzheimer's disease progression and evaluating response to therapy and process for their preparation.
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Page/Page column 6
(2009/05/28)
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- Nucleosidyl-O-methylphosphonates: A pool of monomers for modified oligonucleotides
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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.
- Rejman, Dominik,Masojidkova, Milena,Rosenberg, Ivan
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p. 1683 - 1705
(2007/10/03)
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- TT dinucleotides containing an isoxazoline moiety: Synthesis and binding affinity study
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We have prepared four diastereomers of TT dinucleotides containing an isoxazoline moiety and four dodecanucleotides incorporating these TT dinucleotides in the middle of the DNA sequence. We also have determined the melting temperatures of these modified oligonucleotides (Tm values) by measuring change in UV absorbance.
- Kong, Jong Rock,Kim, Sang Kook,Moon, Byung Jo,Kim, Su Jeong,Kim, Byeang Hyean
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p. 1751 - 1760
(2007/10/03)
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- Synthesis and enzymatic digestion of an RNA nonamer in both enantiomeric forms
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The D- and L-RNA nonamers of the sequence r(GCUUCGGC)T have been synthesised for X-ray crystallographic purposes. In vitro digestion of the unnatural optical antipode by snake venom phosphodiesterase I takes place at an approximately 1800-fold slower rate than that of the natural D-nonamer. The digestion experiments showed - to our knowledge for the first time - that L-RNA can indeed be cleaved enzymatically when phosphodiesterase I from snake venom is used - as opposed to a number of cellular ribonucleases - which sheds an interesting light on the evolution and possibly structure/function relationship of venom versus cellular degradation enzymes. The broad substrate specificity of this enzyme could be taken advantage of to study and further optimise the resistance towards biodegradation of therapeutic L-RNA aptamers. (C) 2000 Elsevier Science Ltd.
- Moyroud, Elisabeth,Biala, Ewa,Strazewski, Peter
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p. 1475 - 1484
(2007/10/03)
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- L-ribonucileosides for racemic RNA
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Two L-ribosyl donors were synthesised from L-xylose, then submitted to a glycosidation reaction according to Vorbruggen's conditions to furnish L- ribonucleosides in high yield.
- Moyroud,Botta,Strazewski
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p. 693 - 695
(2007/10/03)
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- C-3'-branched thymidines as precursors for the selective generation of C-3'-nucleoside radicals
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C-3'-nucleoside radicals can be generated via Norrish type I photocleavage of C-3'-acyl nucleoside derivatives. In monomer experiments employing C-3'-acylthymidine derivatives 2 and 3, a 1:1 mixture of isomers of the H-abstraction products was obtained when the photolysis was carried out in the presence of a hydrogen donor. Derivatives 2 were synthesized by an approach which involves the formation of a silyl-protected cyanohydrin, which is subsequently alkylated with organolithium reagents, followed by hydrolysis. Derivatives 3 could be obtained via a multistep synthesis starting from diol 7. Several different methods were attempted to oxidize the unprotected diol to the α-hydroxy aldehyde. Finally, a route was chosen which involves a protection-deprotection sequence followed by oxidation of the free primary alcohol. The resulting modified nucleosides should facilitate the study of C-3'-DNA radicals.
- Koerner, Steffi,Bryant-Friedrich, Amanda,Giese, Bernd
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p. 1559 - 1564
(2007/10/03)
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- Synthesis of Thymidine Dimers Containing Piperazine in the Internucleoside Linkage and their Incorporation into Oligodeoxynucleotides
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The synthesis of thymidine dimers in which the natural phosphodiester linkage has been replaced by piperazine (3'-(N(CH2CH2)2N)-5, 9 and 3'-(N(CH2CH2)2N)-CO-4, 10) are described.These new dimers were incorporated into oligodeoxynucleotides on an automated DNA-synthesizer using the phosphoramidite approach.The thermal stability of DNA/DNA duplexes and the enzymatic stability was studied by UV experiments. 17-Mers with 9 incorporated once or twice in the middle exhibited a pronounced decrease in thermal stability (ΔTm -11 degC per modification) while 17-mers with 10 incorporated once or twice in the middle exhibited only a slight decrease in thermal stability (ΔTm -2 degC per modification) when compared to unmodified 17-mers.Furthermore, end-modified oligodeoxynucleotides containing either 9 or 10 displayed five to six fold increased stability towards snake venom phosphodiesterase.
- Petersen, Gorm Vang,Wengel, Jesper
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p. 2145 - 2154
(2007/10/02)
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- Enantio- and meso-DNAs: Preparation, characterization, and interaction with complementary nucleic acids
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Enantio-DNAs (DNA having 2-deoxy-L-erythro-pentose, the enantiomer of natural 2-deoxy-D-ribose, as the sugar backbone) and meso-DNAs (DNA having an alternating sequence of L-sugars and D-sugars) were prepared by the use of an automated DNA synthesizer. Th
- Hashimoto, Yuichi,Iwanami, Naoko,Fujimori, Shizuyoshi,Shudo, Koichi
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p. 9883 - 9887
(2007/10/02)
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- 1-(2'-Deoxy-β-D-xylofuranosyl)thymine Building Blocks for Solid-Phase Synthesis and Properties of Oligo(2'-Deoxyxylonucleotides)
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1-(2'-Deoxy-β-D-threo-pentafuranosyl)thymine (= 1-(2'-deoxy-β-D-xylofuranosyl)thymine; xTd; 2) was converted into its phosphonate 3b as well as its 2-cyanoethyl phosphoramidite 3c.Both compounds were used for solid-phase synthesis of d (5), representing the first DNA fragment build up from 3'-5'-linked 2'-deoxy-β-D-xylonucleosides.Moreover, xTd was introduced into the innermost part of the self-complementary dodecamer d(G-T-A-A-xT-xT-C-T-A-C)2 (9).The CD spectrum of d (5) exhibits reversed Cotton effects compared to d(T12) (6; see Fig.1), implying a left-handed single strand.With d(A12) (7) it could be hybridized to form a propably left-handed double strand d(A12)*d (7*5) which was confirmed by melting experiments in combination with temperature-dependent CD spectroscopy.While 5 was hydrolyzed by snake-venom phosphodiesterase, it was resistant towards calf-spleen phosphodiesterase.The modified, self-complementary duplex 9 was hydrolyzed completely by snake-venom phosphodiesterase, at a twelvefold slower rate compared to unmodified 8; calf-spleen phosphodiesterase hydrolyzed 9 only partially.
- Rosemeyer, Helmut,Seela, Frank
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p. 748 - 760
(2007/10/02)
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- PHOSPHORAMIDITES AS SYNTHONS FOR POLYNUCLEOTIDE SYNTHESIS
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Methods for the rapid synthesis of DNA and RNA are described.The procedures involve using nucleoside phosphoramidites as synthons and silica as a polymeric support.Additionally, a novel reaction involving nucleoside O-alkyl methylphosphonothioates is described.
- Caruthers, Marvin H.,Brill, Wolfgang,Dellinger, Douglas J.
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p. 549 - 554
(2007/10/02)
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