cas 40615-39-2, 5'-O-Dimethoxytrityl-deoxythymidine

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Cytotoxic and mutagenic properties of alkyl phosphotriester lesions in Escherichia coli cells
Exposure to many endogenous and exogenous agents can give rise to DNA alkylation, which constitutes a major type of DNA damage. Among the DNA alkylation products, alkyl phosphotriesters have relatively high frequencies of occurrence and are resistant to repair in mammalian tissues. However, little is known about how these lesions affect the efficiency and fidelity of DNA replication in cells or how the replicative bypass of these lesions is modulated by translesion synthesis DNA polymerases. In this study, we synthesized oligodeoxyribonucleotides containing four pairs (Sp and Rp) of alkyl phosphotriester lesions at a defined site, and examined how these lesions are recognized by DNA replication machinery in Escherichia coli cells. We found that the Sp diastereomer of the alkyl phosphotriester lesions could be efficiently bypassed, whereas the Rp counterparts moderately blocked DNA replication. Moreover, the Sp-methyl phosphotriester induced TT→GT and TT→GC mutations at the flanking TT dinucleotide site, and the induction of these mutations required Ada protein, which is known to remove efficiently the methyl group from the Sp-methyl phosphotriester. Together, our study provided a comprehensive understanding about the recognition of alkyl phosphotriester lesions by DNA replication machinery in cells, and revealed for the first time the Ada-dependent induction of mutations at the Sp-methyl phosphotriester site.
Wu, Jiabin,Wang, Pengcheng,Wang, Yinsheng
p. 4013 - 4021
(2018)
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Tetrabutylammonium bromide: An efficient media for dimethoxytritylation of the 5'-hydroxyl function of nucleosides
An efficient procedure for selective dimethoxytritylation of the 5'-hydroxyl function of nucleosides in the presence of DABCO in molten tetrabutylammonium bromide is described. The methodology is very practical, environmentally benign and produced the desired product in less than 5 min by grinding in a hot mortar. In addition, the effects of the room temperature ionic liquid (1-butyl-3-methylimidazolium chloride) and microwave irradiation on this system were also studied and the results showed that depurination of the nucleosides occurred under microwave irradiation.
Khalafi-Nezhad, Ali,Mokhtari, Babak
p. 6737 - 6739
(2004)
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Selective uncaging of DNA through reaction rate selectivity
The synthesis and use of the new nucleobase-caged nucleotides dTpHP and dTNDEACM is reported. Through a combination of time and wavelength selectivity four levels of selective uncaging with only two cages, and only two wavelengths, were obtained. The new residue dTpHP can be uncaged at 313 nm without the formation of unwanted cyclic pyridine dimers.
Rodrigues-Correia, Alexandre,Knapp-Bühle, Diana,Engels, Joachim W.,Heckel, Alexander
p. 5128 - 5131
(2014)
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Synthesis of a convenient thymidine glycol phosphoramidite monomer and its site-specific incorporation into DNA fragments
□ An original phosphoramidite building block of the thymidine glycol lesion has been prepared taking into account the additional diol function and the high lability of this oxidatively induced nucleobase damage. Then the modified nucleoside was site-specifically inserted into DNA fragments by solid support assembling followed by a "one-step" mild final deprotection treatment. Copyright Taylor & Francis Group, LLC.
Gasparutto, Didier,Cognet, Sonia,Roussel, Solveig,Cadet, Jean
p. 1831 - 1842
(2005)
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Synthesis of DNAs with succinamide internucleoside linkages and its application in discrimination of T-C mismatch
Peptide nucleic acid (PNA) has many applications in molecular biology and biotechnology, and research continues on modifying the PNA backbone to improve its functionality. We synthesized PNA in our case, artificial DNA that contains neutral succimamide as internucleoside linkages and applied it to mismatch recognition. We embedded the succinamide linkages into DNA by incorporating thymidine–succinamide–thymidine (TST) phosphoramidite at specific sites via standard DNA synthesis. Ultraviolet spectroscopy and melting temperature experiments suggested that such mixed-backbone DNA forms a B-type duplex with natural DNA. We observed a 20 kJ/mol decrease in enthalpy when we incorporated a succinamide linkage into a DNA–PNA duplex. We examined mismatch recognition of the mixed-backbone DNA, and observed that TST embedded DNA recognizes T-C mismatches.
Sun, Yawei,Lü, Huanfang,Sun, Limei,Wang, Dong,Wang, Jiqian
(2020/11/12)

Synthesis and evaluation of 3′-[18F]fluorothymidine-5′-squaryl as a bioisostere of 3′-[18F]fluorothymidine-5′-monophosphate
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
p. 12423 - 12433
(2021/04/07)

Probing the binding requirements of modified nucleosides with the dna nuclease snm1a
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.
(2021/06/21)

RETRACTED ARTICLE: Divergent synthesis of 5-substituted pyrimidine 2′-deoxynucleosides and their incorporation into oligodeoxynucleotides for the survey of uracil DNA glycosylases
Recent studies have indicated that 5-methylcytosine (5mC) residues in DNA can be oxidized and potentially deaminated to the corresponding thymine analogs. Some of these oxidative DNA damages have been implicated as new epigenetic markers that could have profound influences on chromatin function as well as disease pathology. In response to oxidative damage, the cells have a complex network of repair systems that recognize, remove and rebuild the lesions. However, how the modified nucleobases are detected and repaired remains elusive, largely due to the limited availability of synthetic oligodeoxynucleotides (ODNs) containing these novel DNA modifications. A concise and divergent synthetic strategy to 5mC derivatives has been developed. These derivatives were further elaborated to the corresponding phosphoramidites to enable the site-specific incorporation of modified nucleobases into ODNs using standard solid-phase DNA synthesis. The synthetic methodology, along with the panel of ODNs, is of great value to investigate the biological functions of epigenetically important nucleobases, and to elucidate the diversity in chemical lesion repair.
Tran, Ai,Zheng, Song,White, Dawanna S.,Curry, Alyson M.,Cen, Yana
p. 11818 - 11826
(2020/11/18)

MODIFIED NUCLEOTIDES FOR SYNTHESIS OF NUCLEIC ACIDS, A KIT CONTAINING SUCH NUCLEOTIDES AND THEIR USE FOR THE PRODUCTION OF SYNTHETIC NUCLEIC ACID SEQUENCES OR GENES
A modified nucleotide, intended for the synthesis of long chain nucleic acids by enzymatic processes, comprising a “natural” nitrogenous base or a natural nitrogenous base analogue, a ribose or deoxyribose carbohydrate, and at least one phosphate group, characterized in that said nucleotide comprises at least one R group, termed the modifier group, carried by said nitrogenous base or analogue and/or by the oxygen in position 3′ of the ribose or deoxyribose molecule, making it possible to block the polymerization of said nucleotide and/or to allow the interaction of said nucleotide with another molecule, such as a protein, during the nucleic acid synthesis, R comprising at least one functional terminal group.
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(2020/08/05)

3' PROTECTED NUCLEOTIDES
The present disclosure provides 3' protected nucleotides, including those 3' protected nucleotides having a detectable tag. Systems and methods of sequencing nucleic acids using the 3' protected nucleotides are also disclosed, such as the sequencing of a nucleic acid using a nanopore or the sequencing of a nucleic acid via sequencing-by-synthesis.
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Paragraph 0484-0487

(2020/07/14)

Synthesis of stable azide and alkyne functionalized phosphoramidite nucleosides
The use of CuAAC chemistry to crosslink and stabilize oligonucleotides has been limited by the incompatibility of azides with the phosphoramidites used in automated oligonucleotide synthesis. Herein we report optimized reaction conditions to synthesize azide derivatives of thymidine and cytidine phosphoramidites. Investigation of the stability of the novel phosphoramidites using 31P NMR at room temperature showed less than 10% degradation after 6 h. The azide modified thymidine was successfully utilized as an internal modifier in the standard phosphoramidite synthesis of a DNA sequence. The synthesized azide and alkyne derivatives of pyrimidines will allow efficient incorporation of azide and alkyne click pairs into nucleic acids, thus widening the applicability of click chemistry in investigating the chemistry of nucleic acids.
Lingala, Suresh,Nordstr?m, Lars Ulrik,Mallikaratchy, Prabodhika R.
supporting information
p. 211 - 213
(2019/01/04)

REACTIVE, LIPOPHILIC NUCLEOSIDE BUILDING BLOCKS FOR THE SYNTHESIS OF HYDROPHOBIC NUCLEIC ACIDS
The present invention relates to a method for the isolation and/or identification of known or unknown sequences of nucleic acids (target sequences) optionally marked with reporter groups by base specific hybridation with complementary sequences using nucleolipids. The nucleolipids are prepared by lipophilizing nucleosides of formula (Ia) wherein Q represents a group having a substituted tetrahydrofuran ring and Bas represents a group having one or more heterocyclic rings having one or more heterocyclic nitrogen atoms.
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(2019/06/20)

A hydroxamic-acid-containing nucleoside inhibits DNA repair nuclease SNM1A
Nine modified nucleosides, incorporating zinc-binding pharmacophores, have been synthesised and evaluated as inhibitors of the DNA repair nuclease SNM1A. The series included oxyamides, hydroxamic acids, hydroxamates, a hydrazide, a squarate ester and a squaramide. A hydroxamic acid-derived nucleoside inhibited the enzyme, offering a novel approach for potential therapeutic development through the use of rationally designed nucleoside derived inhibitors.
Doherty, William,Dürr, Eva-Maria,Baddock, Hannah T.,Lee, Sook Y.,McHugh, Peter J.,Brown, Tom,Senge, Mathias O.,Scanlan, Eoin M.,McGouran, Joanna F.
supporting information
p. 8094 - 8105
(2019/09/19)

Compound, fluorescence-labeled-introducing agent, and introducing fluorescent labeling method (by machine translation)
[Problem] no fluorescence whereas the extracellular, intracellular fluorescence of fluorescently labeled compound is incorporated, and such fluorescent labeling for introducing fluorescent labeling agent is introduced. (1) A compound represented by general formula [a] is used. In the general formula (1), the A, biological material or derivatives thereof may be incorporated into the cell through a cell membrane structure 1 comprises a divalent group, the FL, fluorescent light having a fluorescent unit which exhibits cyclic backbone nitrogen atom, L is, a monovalent group FL A coupling 2, the X, a single bond or O - (=O) a - C, wavy lines represent bonds, the nitrogen atom is bound to a FL included, the Ar, para or ortho position of the aromatic ring which has a valence bond 2, R is, nitro or - S e S a-R1 And, R1 Is, a monovalent group, n the, an integer of 1 - 3. [Drawing] no (by machine translation)
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(2020/01/07)

Polymerizable Compound, Compound, and Method for Producing Boranophosphate Oligomer
Provided a polymerizable compound represented by the following Formula A-1 or Formula A-2: In Formula A-1 or Formula A-2, R1 represents an electron-donating group; n represents an integer from 1 to 5; R2 represents a hydrogen atom, a halogen atom, or —ORO, wherein RO represents a hydrogen atom, an alkyl group, or a protecting group of a hydroxy group; R3 represents a hydrogen atom or a protecting group of a hydroxy group; and X represents a structure represented by any one of Formula B-1 to Formula B-5.
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(2019/09/16)

Renewable amberlyst-15 catalyzed highly regioselective tritylation and deprotection of sugar-based diols
Amberlyst-15 catalyzed highly regioselective tritylation of sugar-based diols was achieved under mild condition using 4,4′-dimethoxytrityl alcohol (DMTrOH). Deprotection of the corresponding DMTr group was also established by the variation to protic solvent. Meanwhile, the heterogeneous catalyst Amberlyst-15 was recycled 3 times with satisfactory retention of catalytic activity and proved its potential application in industry.
Valeru, Anil,Luo, Zhibin,Penjarla, Srishylum,Khan, Imran,Liu, Bin,Sngepu, Bhavanarushi,Xu, Yin,Xie, Jimin
p. 318 - 326
(2018/10/15)

Synthesis of 2-deoxy ribose related disaccharide nucleoside and its phosphoramidite
Synthesis of impurity reference compound of anti-tumor drug ISIS 183750 was achieved. In this process, a general method for synthesis of 2-deoxy ribosyl disaccharide nucleosides was established for the first time.
Ding, Yili,Deng, Rilie,Wang, Bingyun
p. 3848 - 3852
(2017/06/13)

Tritylation of alcohols under mild conditions without using silver salts
Secondary alcohols were conveniently tritylated under mild conditions within a short running time with tritylium trifluoroacetate generated in situ from trityl alcohols and trifluoroacetic anhydride. No expensive silver salts were needed for the reactions. Four secondary alcohols were tritylated with both mono- and dimethoxy trityl alcohols giving good to excellent isolated yields. The reaction was also tested on four nucleoside derivatives that have primary alcohols. Satisfactory results were also obtained.
Shahsavari, Shahien,Chen, Jinsen,Wigstrom, Travis,Gooding, James,Gauronskas, Alexander,Fang, Shiyue
supporting information
p. 3877 - 3880
(2016/08/02)

Intermolecular 'cross-torque': The N4-cytosine propargyl residue is rotated to the 'CH'-edge as a result of Watson-Crick interaction
Propargyl groups are attractive functional groups for labeling purposes, as they allow CuAAC-mediated bioconjugation. Their size minimally exceeds that of a methyl group, the latter being frequent in natural nucleotide modifications. To understand under which circumstances propargyl-containing oligodeoxynucleotides preserve base pairing, we focused on the exocyclic amine of cytidine. Residues attached to the exocyclic N4 may orient away from or toward the Watson-Crick face, ensuing dramatic alteration of base pairing properties. ROESY-NMR experiments suggest a uniform orientation toward the Watson-Crick face of N4-propargyl residues in derivatives of both deoxycytidine and 5-methyl-deoxycytidine. In oligodeoxynucleotides, however, UV-melting indicated that N4-propargyl-deoxycytidine undergoes standard base pairing. This implies a rotation of the propargyl moiety toward the 'CH'-edge as a result of base pairing on the Watson-Crick face. In oligonucleotides containing the corresponding 5-methyl-deoxycytidine derivative, dramatically reduced melting temperatures indicate impaired Watson-Crick base pairing. This was attributed to a steric clash of the propargyl moiety with the 5-methyl group, which prevents back rotation to the 'CH'-edge, consequently preventing Watson-Crick geometry. Our results emphasize the tendency of an opposing nucleic acid strand to mechanically rotate single N4-substituents to make way for Watson-Crick base pairing, providing no steric hindrance is present on the 'CH'-edge.
Domingo, Olwen,Hellmuth, Isabell,J?schke, Andres,Kreutz, Christoph,Helm, Mark
p. 5275 - 5283
(2015/07/15)

Synthesis of novel cationic spermine-conjugated phosphotriester oligonucleotide for improvement of cell membrane permeability
A spermine-conjugated ethyl phosphotriester oligonucleotide was obtained by solid-phase synthesis based on phosphoramidite chemistry. The ethyl phosphotriester linkage was robust to exonuclease digestion and stable in fetal bovine serum. Cell membrane permeability of the spermine-conjugated ethyl phosphotriester oligonucleotide was studied by fluorescence experiments. The effective cell penetrating potency of the spermine-conjugated ethyl phosphotriester oligonucleotide was determined by confocal laser scanning microscopy and measurement of intracellular fluorescence intensity.
Hayashi, Junsuke,Hamada, Tomoko,Sasaki, Ikumi,Nakagawa, Osamu,Wada, Shun-Ichi,Urata, Hidehito
p. 3610 - 3615
(2015/08/11)

Red light-controlled polymerase chain reaction
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
p. 13324 - 13326
(2015/08/24)

Reactive, lipophilic nucleoside building blocks for the synthesis of hydrophobic nucleic acids
The present invention relates to a method for the isolation and/or identification of known or unknown sequences of nucleic acids (target sequences) optionally marked with reporter groups by base specific hybridation with, essentially, complementary sequences (in the following referred to as sample oligonucleotides, sample sequences or sample nucleic acids), which belong to a library of sequences. Further, the invention relates to nucleolipids used in the method of the invention and a process for the preparation of said nucleolipids.
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(2014/05/06)

Synthesis of functionalized lipids, and their use for a tunable hydrophobization of nucleosides and nucleic acids
Two series of functionalized single and double side-chained lipid molecules (Schemes 1 and 2) were prepared. The compounds carry either terminal COOH, OH, or halogen substituents. Moreover, the double side-chained lipid 18 carries an internal alkyne functionality. The latter compound was used to hydrophobize thymidine at N(3) by base-catalyzed alkylation. Additionally, fully protected thymidine, 32, was N(3)-alkylated with the double side-chained alcohol 9 applying Mitsunobu reaction conditions. Copyright
Korneev, Sergei,Rosemeyer, Helmut
p. 201 - 216
(2013/03/28)

Novel method of the synthesis and hybridization properties of an oligonucleotide containing non-ionic diisopropylsilyl internucleotide linkage
Efficient synthesis of a dithymidine dinucleotide analog bearing a diisopropylsilyl linkage instead of a phosphodiester linkage is described with respect to its incorporation into oligonucleotides. The diisopropylsilyl linkage was introduced into the oligonucleotide by preparation of the phosphoramidite derivative of a dithymidine dimer unit. The diisopropylsilyl-modified oligonucleotide exhibited hybridization behavior with both single strand and duplex DNA. The thermal stability of both the duplex and triplex showed a relative instability compared to the corresponding natural phosphodiester DNA, because of the steric hindrance of the isopropyl group on the silicon atom.
Moriguchi, Tomohisa,Sekine, Mitsuaki,Shinozuka, Kazuo
p. 8013 - 8018
(2014/01/06)

Synthesis of thymidine, uridine, and 5-methyluridine nucleolipids: Tools for a tuned lipophilization of oligonucleotides
Three pyrimidine nucleosides, uridine (1), 5-methyluridine (6), and 2′-deoxythymidine (11), were converted to amphiphilic nucleolipids. Compounds 1 and 6 were lipophilized by introduction of symmetric ketal moieties with various carbon chain lengths (i.e., 5-17). Two ketal derivatives, 2b and 7a, were additionally further hydrophobized by N(3)-farnesylation. 2′-Deoxythymidine was alkylated at N(3) with a cetyl (=hexadecyl) residue, either directly or, after complete orthogonal protection of the sugar OH groups, by Mitsunobu reaction with hexadecan-1-ol. Some of the nucleolipids were subsequently converted to their 2-cyanoethyl phosphoramidites (5′ or 3′), one of which was used for an exemplary synthesis of a lipo-oligonucleotide. The sequence of this lipo-oligonucleotide is an encoded manifestation of Pythagoras' law, created with a key table in which the letters of the alphabet, the numbers from 0 to 9 as well as the mostly used mathematical symbols are allocated to a ribonucleic acid triplet of the genetic code. Copyright
Werz, Emma,Viere, Rebecca,Gassmann, Gina,Korneev, Sergei,Malecki, Edith,Rosemeyer, Helmut
p. 872 - 888
(2013/07/05)

A TT dinucleotide with a nonionic silyl backbone: Impact on conformation and h-bond mediated base pairing as studied by low-temperature NMR
A TSiT dinucleotide linked through a nonionic diisopropylsilyl backbone has been synthesized and studied for its self-association through base-base recognition together with a free thymidine nucleoside. To characterize hydrogen-bonded associates in more detail, NMR measurements were performed in a freonic solvent at temperatures as low as 113 K in the slow hydrogen bond exchange regime. For the thymidine, TT base pairs with both the 2- and 4-carbonyl engaged in hydrogen bonds to the imino proton were observed. Whereas hydrogen bonds to the O4 acceptor are stronger as evidenced by a more deshielded proton in the hydrogen bridge when compared to hydrogen bonds to the O2 acceptor, the latter is nevertheless slightly favored over O4 in the H-bond formation of TT base pairs. The diisopropylsilyl linkage of the TSiT dinucleotide has no significant impact on the geometry and strength of formed NH-O2 and NH-O4 hydrogen bonds indicating, that the silyl backbone does not compromise the alignment of bases and does not pose any restrictions to the cyclic hydrogen bond formation between thymidines of the two strands. However, NMR results point to an exclusive formation of TSiT duplexes with an antiparallel strand orientation. by Oldenbourg Wissenschaftsverlag, Mu?nchen.
Janke, Eline M. Ba?ilio,Weisz, Klaus
p. 791 - 806
(2013/08/23)

Expanding the horizon of the thymine Isostere biochemistry: Unique cyclobutane dimers formed by photoreaction between a thymine and a toluene residue in the dinucleotide framework
Substituted toluenyl groups are considered as close isosteres of the thymine residue. They can be recognized by DNA polymerases as if they were thymine. These toluene derivatives are generally inert toward radical additions, including the [2+2] photocycloadditions, due to the stable structure of the aromatic ring and are usually used as solvents for radical reactions. Surprisingly, after incorporating toluene into the dinucleotide framework, we found that the UV excited thymine residue readily dimerizes with the toluenyl moiety through a [2+2] photoaddition reaction. Furthermore, the reaction site on the toluenyl moiety is not the C5=C6 bond, as commonly observed in cyclobutane pyrimidine dimers, but the C4=C5 or C3=C4 instead. Such a reaction pattern suggests that in the stacked structure, it is one of these bonds, not the C5=C6, that is close to the thymine C5=C6 bond. A similar structural feature is found in DNA duplex with a thymine replaced by a 2,4-difluorotoluene. Our results argue that although the substituted toluenyl moieties closely mimic the size and shape of the thymine residue, their more hydrophobic nature determines that they stack on DNA bases differently from the natural thymine residue and likely cause local conformational changes in duplex DNA.
Liu, Degang,Zhou, Yan,Pu, Jingzhi,Li, Lei
experimental part
p. 7823 - 7833
(2012/10/07)

Synthesis of thymidine dimers from 5′-O-aminothymidine
The synthesis of modified oligonucleotides is of great importance for various therapeutic and diagnostic applications. The facile secondary structure formation of N-oxyamide-linked peptide analogues and the high nucleophilicity of the aminooxy function prompted us to prepare O-amino nucleoside derived dinucleosides. Herein, the efficient synthesis of three novel thymidine dimers with N-oxyamide, oxime and oxyamine linkages via a convergent approach from a common 5-O-aminothymidine is reported. Georg Thieme Verlag Stuttgart · New York.
Peyrat, Sandrine,Xie, Juan
experimental part
p. 1718 - 1724
(2012/08/08)

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
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
supporting information; experimental part
p. 2649 - 2671
(2012/06/16)

Novel thermolabile protecting groups with higher stability at ambient temperature
Novel thermolabile hydroxyl protecting groups of increased thermostability are proposed. The stability of these groups at different temperatures ranges has been determined. The 2-pyridyl-N-(2,4-difluorobenzyl)aminoethyl unit was selected as stable at ambient temperature and very labile at increased temperature. The half-life times for the best groups were established. Application of this chemistry to the protection of different hydroxyl groups of thymidine was also demonstrated.
Chmielewski, Marcin K.
supporting information; experimental part
p. 666 - 669
(2012/02/15)

Improved synthesis of 5-hydroxymethyl-2′-deoxycytidine phosphoramidite using a 2′-deoxyuridine to 2′-deoxycytidine conversion without temporary protecting groups
5-Hydroxymethylcytosine has recently been characterized as the 'sixth base' in human DNA. To enable research on this DNA modification, we report an improved method for the synthesis of 5-hydroxymethyl-2′-deoxycytidine (5-HOMedC) phosphoramidite for site-specific incorporation into oligonucleotides. To minimize manipulations we employed a temporary protecting group-free 2′-deoxyuridine to 2′-deoxycytidine conversion procedure that utilizes phase transfer catalysis. The desired 5-HOMedC phosphoramidite is obtained in six steps and 24% overall yield from 2′-deoxyuridine.
Hansen, Anders S.,Thalhammer, Armin,El-Sagheer, Afaf H.,Brown, Tom,Schofield, Christopher J.
supporting information; experimental part
p. 1181 - 1184
(2011/04/16)

Synthesis of covalently linked parallel and antiparallel DNA duplexes containing the metal-mediated base pairs T-Hg(ii)-T and C-Ag(i)-C
DNA duplexes fixed in anti-parallel and parallel orientations by introducing covalent linkages have been synthesized and metal ions, Hg(ii) and Ag(i), were incorporated into pyrimidine-pyrimidine base pairs.
Ono, Takashi,Yoshida, Kyohei,Saotome, Yuko,Sakabe, Rei,Okamoto, Itaru,Ono, Akira
supporting information; experimental part
p. 1542 - 1544
(2011/03/22)

A divalent metal-dependent self-cleaving DNAzyme with a tyrosine side chain
The enzymatic incorporation of a phenol-modified 2′-deoxyuridine triphosphate gave rise to a modified DNA library that was subsequently used in an in vitro selection for ribophosphodiester-cleaving DNAzymes in the presence of divalent zinc and magnesium cations. After 11 rounds of selection, cloning and sequencing resulted in 14 distinct sequences, the most active of which was Dz11-17PheO. Dz11-17PheO self-cleaved an embedded ribocytidine with an observed rate constant of 0.20 ± 0.02 min-1 in the presence of 10 mM Mg2+ and 1 mM Zn2+ at room temperature. The activity was inhibited at low concentrations of Hg2+ cations and somewhat higher concentrations of Eu3+ cations.
Lam, Curtis H.,Hipolito, Christopher J.,Hollenstein, Marcel,Perrin, David M.
supporting information; experimental part
p. 6949 - 6954
(2011/11/05)

Synthesis, cytotoxicity, and insight into the mode of action of Re(CO) 3 thymidine complexes
Nucleoside analogues are extensively used in the treatment of cancer and viral diseases. The antiproliferative properties of organorhenium(I) complexes, however, have been scarcely explored to date. Herein we present the syntheses, characterization, and in vitro evaluation of ReI(CO)3 core complexes of thymidine and uridine. For the binding of the Re I(CO)3 core, a tridentate dipicolylamine metal chelate was introduced at positions C5′, C2′, N3, and C5 with spacers of various lengths. The corresponding organometallic thymidine complexes were fully characterized by IR and NMR spectroscopy and mass spectrometry. Their cytotoxicity was assessed against the A549 lung carcinoma cell line. Toxicity is dependent on the site and mode of conjugation as well as on the nature and the length of the tether. Moderate toxicity was observed for conjugates carrying the rhenium moiety at position C5′ or N3 (IC50=124-160 μm). No toxicity was observed for complexes modified at C2′ or C5. Complex 53, with a dodecylene spacer at C5′, exhibits remarkable toxicity and is more potent than cisplatin, with an IC50 value of 6.0 μm. To the best of our knowledge, this is the first report of the antiproliferative properties of [M(CO)3]+1-nucleoside conjugates. In competitive inhibition experiments with A549 cell lysates and purified recombinant human thymidine kinase 1 (hTK-1), enzyme inhibition was observed for complexes modified at either N3 or C5′, but our results suggest that the toxicity cannot be attributed solely to interaction with hTK-1.
Bartholomae, Mark D.,Vortherms, Anthony R.,Hillier, Shawn,Ploier, Birgit,Joyal, John,Babich, John,Doyle, Robert P.,Zubieta, Jon
experimental part
p. 1513 - 1529
(2011/11/29)

Base-base recognition of nonionic dinucleotide analogues in an apolar environment studied by low-temperature NMR spectroscopy
Two self-complementary dinucleotide analogues TSiA and A si with a nonionic diisopropylsilyl-modified backbone were synthesized, and their association in a nonaqueous aprotic environment was studied by NMR spectroscopy. Using a CDClF2/CDF3 solvent mixture, measurements at temperatures as low as 113 K allowed the observation and structural characterization of individual complexes in the slow exchange regime. The AsiT analogue associates to exclusively form a dinucleotide antiparallel duplex with regular Watson-Crick base pairing, but both A and T nucleosides exhibit a predominant C3'-endo sugar pucker reminiscent of an A-type conformation. In contrast to AsiT the TSiA dinucleotide is found to exhibit significant variability and flexibility. Thus, different secondary structures with weaker hydrogen bonds for all T SiA structures are observed at low temperatures. Although a B-like Watson-Crick antiparallel dinucleotide duplex with a preferred C2'-endo sugar pucker largely predominates at temperatures above 153 K, two additional species, namely a dinucleotide Hoogsteen duplex with a syn glycosidic torsion angle of the adenosine nucleoside and a presumably intramoleculariy folded structure, are increasingly populated upon further cooling. By adding typical DNA intercalators like anthracene or benz[c]acridine derivatives to the A siT dinucleotide duplex in the aprotic solvent environment, no binding of the polycyclic aromatic molecules can be detected even at lower temperatures. Obviously, van der Waals and stacking interactions are insufficient to compensate for the other unfavorable contributions to the overall free energy of binding, and only in the presence of additional hydrophobic effects in an aqueous environment does binding occur.
Xiao, Zhou,Weisz, Klaus
scheme or table
p. 3862 - 3869
(2010/05/15)

Solid-phase synthesis of oligodeoxynucleotides containing N 4-[2-(t-butyldisulfanyl)ethyl]-5-methylcytosine moieties
An efficient route for the synthesis of the phosphoramidite derivative of 5- methylcytosine bearing a tert-butylsulfanyl group protected thiol is described. This building block is used for the preparation of oligonucleotides carrying a thiol group at the nucleobase at the internal position of a DNA sequence. The resulting thiolated oligonucleotides are useful intermediates to generate oligonucleotide conjugates carrying molecules of interest at internal positions of a DNA sequence.
Perez-Rentero, Sonia,Garibotti, Alejandra V.,Eritja, Ramon
scheme or table
p. 5692 - 5707
(2010/12/24)

STABILISATION OF RADIOPHARMACEUTICAL PRECURSORS
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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(2010/02/17)

Radiologic Agents for Monitoring Alzheimer's Disease Progression and Evaluating a Response to Therapy and Processes for the Preparation of Such Agents
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 9-11

(2009/05/28)

Photolabile protection of alcohols, phenols, and carboxylic acids with 3-hydroxy-2-naphthalenemethanol
(Chemical Equation Presented) Irradiation of alcohols, phenols, and carboxylic acids "caged" with the (3-hydroxy-2-naphthalenyl)methyl group results in fast (krelease ≈ 105 s-1) release of the substrates with good quantum (Φ = 0.17-0.26) and chemical (>90%) yields. The initial byproduct of the photoreaction, 2-naphthoquinone-3-methide, reacts rapidly with water (kH2O = 144 ± 11 s-1) to produce parent 3-hydroxy-2-naphthalenemethanol. The o-quinone methide intermediate can be also trapped by other nucleophiles or converted into a photostable Diels-Alder adduct with ethyl vinyl ether.
Kulikov, Anton,Arumugam, Selvanathan,Popik, Vladimir V.
p. 7611 - 7615
(2008/12/22)

NUCLEOSIDE BASED PROLIFERATION IMAGING MARKERS
Disclosed herein are novel radiolabeled nucleosides and methods for detecting cellular proliferation in a mammal, the method comprising administrating an effective amount of a radiolabeled nucleoside; the method comprising: a) administering to the mammal a diagnostically effective amount of the nucleoside to the mammal; b) allowing the nucleoside to distribute into the effective tissue; and c) imaging the tissue, wherein an increase in binding of the compound to tissue compared to a normal control level of binding indicates that the mammal is suffering from a disease involving cellular proliferation.
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Page/Page column 49

(2008/12/08)

Technetium-99m-labeling and synthesis of thymidine analogs: Potential candidates for tumor imaging
The technetium-99m-labeling and synthesis of a series of thymidine analogs were studied. The target molecules were obtained by using 6-hydrazinopyridine-3-carboxylic acid (HYNIC) as a bifunctional coupling agent and using N-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)glycine (tricine) and ethylenediamine-N,N′-diacetic acid (EDDA) as coligands. The effects of different spacers between thymidine analog with HYNIC on radiochemical yield were also studied.
Teng, Bao,Bai, Yunpeng,Chang, Yu,Chen, Shizhen,Li, Zhaolong
p. 3440 - 3444
(2008/02/10)

Synthesis of 3′-S-phosphorothiolate oligonucleotides for their potential use in RNA interference
The potency of RNA interference (RNAi) undoubtedly can be improved through chemical modifications to the small interfering RNAs (siRNA). By incorporation of the 3′-S-phosphorothiolate modification into strands of RNA, it is hoped that specific regions of a siRNA duplex can be stabilised to enhance the target binding affinity of a selected antisense strand into the activated RNA-induced silencing complex (RISC*). Oligonucleotides composed entirely of this modification are desirable so unconventional 5′ → 3′synthesis is investigated, with initial solution-phase testing proving successful. The phosphoroamidite monomer required for solid-phase synthesis has also been produced. Copyright Taylor & Francis Group, LLC.
Gaynor, James W.,Brazier, John,Cosstick, Rick
p. 709 - 712
(2008/03/27)

2-(Phenylthio)ethyl as a novel two-stage base protecting group for thymidine analogues
2-(Phenylthio)ethyl is here proposed for temporary masking the thymine residue in the synthesis of sugar modified thymidine derivatives. This protection has been devised as a 'two-stage' system. The 2-(phenylthio)ethyl residue can be easily and regiospecifically inserted at the N3-position of the pyrimidine by a Mitsunobu reaction with 2-(phenylthio)ethanol and is perfectly stable also to strongly basic conditions. This allowed us to selectively achieve O-alkylation of the ribose moieties in satisfactory yields, avoiding undesired base alkylations. After oxidation of the thioether to sulfone, the thymine protecting group can be totally removed, by a β-elimination mechanism, upon the same basic treatment required for the final deprotection and detachment of oligonucleotides from the support in solid-phase synthesis protocols. Georg Thieme Verlag Stuttgart.
D'Onofrio, Jennifer,De Napoli, Lorenzo,Di Fabio, Giovanni,Montesarchio, Daniela
p. 845 - 848
(2007/10/03)

Functional synthetic molecules and macromolecules for gene delivery
The present invention describes a synthetic non-viral vector composition for gene therapy and the use of such compositions for in vitro, ex vivo and/or in vivo transfer of genetic material. The invention proposes a pharmaceutical composition containing 1) a non-cationic amphiphilic molecule or macromolecule and its use for delivery of nucleic acids or 2) a cationic amphiphilic molecule or macromolecule that transforms from a cationic entity to an anionic, neutral, or zwitterionic entity by a chemical, photochemical, or biological reaction and its use for delivery of nucleic acids. Moreover this invention describes the use of these non-viral vector compositions in conjunction with a surface to mediate the delivery of nucleic acids. An additional embodiment is the formation of a hydrogel with these compositions and the use of this hydrogel for the delivery of genetic material. A further embodiment of this invention is the use of a change in ionic strength for the delivery of genetic material.
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Page/Page column 48

(2008/06/13)

Efficient large-scale synthesis of 5′-O-dimethoxytrityl-N 4-benzoyl-5-methyl-2′-deoxycytidine
An efficient process to synthesize 5′- O -dimethoxytrityl-N 4 -benzoyl-5-methyl-2 ′-deoxycytidine in high yield and quality is described. Final benzoylation was improved by developing a method to selectively hydrolyze benzoyl ester impurities. This inexpensive approach was scaled up to multi-kilogram quantities for routine use in oligonucleotide therapeutics. Copyright Taylor & Francis Group, LLC.
Ross, Bruce,Han, Mingming,Ravikumar, Vasulinga
p. 765 - 770
(2007/10/03)

Modulation of DC-SIGN expression
Compounds, compositions and methods are provided for modulating the expression of DC-SIGN. The compositions comprise oligonucleotides, targeted to nucleic acid encoding DC-SIGN. Methods of using these compounds for modulation of DC-SIGN expression and for diagnosis and treatment of diseases and conditions associated with expression of DC-SIGN are provided.
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Page/Page column 12

(2008/06/13)

Antisense modulation of polo-like kinase expression
Antisense compounds, compositions and methods are provided for modulating the expression of polo-like kinase. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding polo-like kinase. Methods of using these compounds for modulation of polo-like kinase expression and for treatment of diseases associated with expression of polo-like kinase are provided.
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Page/Page column 16-17

(2008/06/13)

Synthesis of beta-L-2'-deoxy nucleosides
An improved process for the preparation of 2′-modified nucleosides and 2′-deoxy-nucleosides, such as, β-L-2′-deoxy-thymidine (LdT), is provided. In particular, the improved process is directed to the synthesis of a 2′-deoxynucleoside that may utilize different starting materials but that proceeds via a chloro-sugar intermediate or via a 2,2′-anhydro-1-furanosyl-nucleobase intermediate. Where an 2,2′-anhydro-1-furanosyl base intermediate is utilized, a reducing agent, such as Red-Al, and a sequestering agent, such as 15-crown-5 ether, that cause an intramolecular displacement reaction and formation of the desired nucleoside product in good yields are employed. An alternative process of the present invention utilizes a 2,2′-anhydro-1-furanosyl base intermediate without a sequestering agent to afford 2′-deoxynucleosides in good yields. The compounds made according to the present invention may be used as intermediates in the preparation of other nucleoside analogues, or may be used directly as antiviral and/or antineoplastic agents.
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Page/Page column 42; 43

(2010/02/11)

Antisense inhibition via RNAse H-independent reduction in mRNA
The present invention provides compositions and methods for reducing levels of a preselected mRNA, using antisense compounds targeted to a splice site or a region up to 50 nucleobases upstream of an exon/intron junction on said mRNA. Preferably, said antisense compounds do not elicit RNAse H cleavage of the mRNA.
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Page/Page column 16

(2010/02/12)

Nucleosidyl-O-methylphosphonates: A pool of monomers for modified oligonucleotides
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
p. 1683 - 1705
(2007/10/03)

Modulation of diacylglycerol acyltransferase 1 expression
Compounds, compositions and methods are provided for modulating the expression of diacylglycerol acyltransferase 1. The compositions comprise oligonucleotides, targeted to nucleic acid encoding diacylglycerol acyltransferase 1. Methods of using these compounds for modulation of diacylglycerol acyltransferase 1 expression and for diagnosis and treatment of disease associated with expression of diacylglycerol acyltransferase 1 are provided.
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Page/Page column 12

(2008/06/13)