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SYNTHESIS AND IMPROVEMENT OF A NUCLEOSIDE ANALOGUE AS AN ANTI-CANCER AND ANTI-VIRAL DRUG
The invention is a drug for anticancer and antiviral therapy, comprising a nucleoside analogue (7) comprising a furan ring irreversibly bound to the RNA/DNA synthesis chain by phosphodiester bonds and having SP3 hybridization, and folic acid (A) bound to the nucleoside analogue (7) comprising furan ring. The synthesis method of the said nucleoside analogue is also contained within the scope of the invention. In this work, a nucleoside-analogue was transformed after converting the furan-ring hybridization from Sp2 to Sp3 to make it more selectivity with different enzymes and linking it via site 5 with the effective folic acid towards entering the substances inside the cells and to become the final compound possessing anti-cancer and anti- virus properties after controlling the replication and reproduction process in DNA.
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(2021/05/29)

Synthesis and photophysical properties of 5-(3′′-alkyl/aryl-amino-1′′-azaindolizin-2′′-yl)-2′-deoxyuridines
The Groebke-Blackburn-Bienayame (GBB) reaction has been used for the efficient synthesis of novel fluorescent 5-azaindolizino-2′-deoxyuridines starting from commercially available thymidine following two strategies. Thus, thymidine was converted to diacetylthymidine, which on potassium persulphate oxidation afforded 3′,5′-di-O-acetyl-5-formyl-2′-deoxyuridine. In strategy A, diacetylated 5-formyldeoxyuridine was reacted with a variety of 2-aminopyridines and alkyl/aryl isocyanides under optimized GBB reaction conditions followed by deacetylation of the resulting GBB products to afford 5-azaindolizino-2′-deoxyuridines in 83 to 95% overall yields. In strategy B, diacetylated 5-formyldeoxyuridine was first deacetylated, which on GBB reaction under standardised conditions with 2-aminopyridines and alkyl/aryl isocyanides afforded the desired 5-azaindolizino-2′-deoxyuridines in 21 to 23% overall yields, which clearly indicates that strategy A is far more efficient than strategy B. The emission spectra of the synthesized 5-azaindolizino-2′-deoxyuridines exhibited a strong band around 360 nm (excitation at 239 nm) in fluorescence studies. Photophysical studies of these nucleosides showed a high level of fluorescence with Stokes shift in the range 59-126 nm, which indicated their potential for the study of the local structure and dynamics of nucleic acids involving them.
Bali Mehta, Shilpika,Kumar, Banty,Kumar, Sandeep,Kumar, Sumit,Maity, Jyotirmoy,Prasad, Ashok K.
p. 16635 - 16647
(2021/09/27)

4 - Thiodeoxythymidine derivative and anti-hepatitis B virus pharmaceutical application thereof
4 - Thio-deoxythymidine derivatives and anti-hepatitis B virus pharmaceutical applications thereof are disclosed. The invention provides 4 - thiodeoxythymidine derivative or a pharmaceutically acceptable salt thereof, and the structure is shown in structural formula I or structural formula II. An in-vitro cytotoxicity test and an in-vitro anti HBV virus pharmacodynamic test proves 4 - thiodeoxythymidine derivative or a pharmaceutically acceptable salt thereof has anti HBV activity, has an anti-hepatitis B drug development prospect and provides a potential choice for treating viral hepatitis.
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Paragraph 0043-0044

(2021/10/05)

A synergistic synthetic and computational insights towards anomerization of N-nitro pyrimidine nucleosides using fluorinating agents
DAST and Deoxofluor are usually used for nucleophilic fluorination of nucleosides via SN1 or SN2 mechanism. DAST and Deoxo-fluor could enhance anomerization of N-substituted thymidine and 2′-deoxyuridine in dichloromethane into the more stable and favored α-anomers due to in-situ liberation of HF. This is strongly supported by computational calculations based on the density functional theory, that were performed to rationalize energy stability and electronic properties of both anomers in order to provide further insights into the proposed mechanism.
Bayach, Imene,Khalil, Ahmed,Mathé, Christophe
(2020/03/18)

Light-Induced Formation of Thymine-Containing Mercury(II)-Mediated Base Pairs
By applying caged thymidine residues, DNA duplexes were created in which HgII-mediated base pair formation can be triggered by irradiation with light. When a bidentate ligand was used as the complementary nucleobase, an unprecedented stepwise formation of different metal-mediated base pairs was achieved.
Naskar, Shuvankar,Müller, Jens
supporting information
p. 16214 - 16218
(2019/11/26)

Syntheses of C-6 Aryl- and Alkynyl-Substituted Thymidines from Thymidine trans-5,6-Bromohydrins
C-6-substituted thymidines are biochemically important compounds. The thymidine (6–4) photoproduct [i.e., 5-hydroxy-6-(thymidine-4-yl) dihydrothymidine], in particular, is a DNA lesion that is triggered by the UV irradiation of sunlight. Herein, we report a metal-free cis-diastereoselective ring opening of thymidine 5,6-epoxides by using mildly nucleophilic organofluoroborates in the presence of BF3·Et2O to provide facile access to (6–4) photoproduct analogues. A broad range of aryl and alkynylfluoroborates are compatible with the reaction conditions, which also tolerate various protecting groups. Furthermore, the epoxide addition products can undergo a thionyl chloride/pyridine promoted dehydration process to give the respective pharmaceutically attractive C-6-substituted thymidines in high yields, thus providing a new and straightforward method for their synthesis.
Wrigstedt, Pauli,Iashin, Vladimir,Lagerblom, Kalle,Keskiv?li, Juha,Chernichenko, Konstantin,Repo, Timo
p. 880 - 891
(2017/02/15)

Biocatalytic Process Optimization for the Production of High-Added-Value 6-O-Hydroxy and 3-O-Hydroxy Glycosyl Building Blocks
A biocatalytic process to synthesize regioselective monohydroxy glycosyl building blocks has been optimized. Lipases immobilized on commercial supports were treated with water-soluble carbodiimide (EDC) at different concentrations. In the presence of cosolvents, the stability of lipases adsorbed on octyl-Sepharose improved after the EDC modification. The new Candida rugosa lipase (CRL) modified heterogeneous biocatalysts were tested in the production of 6-OH hydroxyl-tetraacetyl glucose by a regioselective mono-deacetylation in aqueous media. Improvements in activity and excellent regioselectivity were obtained for octyl-CRL-EDC10mM preparation, with 95 % isolated yield of product on a multimilligram scale. We also observed excellent recyclability. The C-6 alcohol was transformed to a C-3 alcohol by chemical migration, and both compounds were transformed successfully in the corresponding new trichloroacetimidyl glucoderivatives. Modified CRL biocatalysts were also tested in the selective deprotection of peracetylated thymidine, and octyl-CRL-EDC10mM showed excellent specificity and improved regioselectivity to produce 3-hydroxy-5-acetyl-thymidine, a precursor of azidethymidine (AZT), in 95 % yield. The new Rhizomucor miehei lipase (RML)-modified heterogeneous biocatalysts showed excellent regioselectivity and recyclability in the 3-OH mono-deprotection of peracetylated lactal.
Callaghan, Ciara,Redmond, Martin,Alnoch, Robson Carlos,Mateo, Cesar,Filice, Marco,Palomo, Jose M.
p. 2536 - 2543
(2017/07/13)

Synthesis of novel caged antisense oligonucleotides with fluorescence property
In this study, novel caged antisense oligonucleotides with thiochromone S,S-dioxide as the photolabile protecting group were synthesized, and their photodeprotection was investigated. In vitro experiment, the original target molecule was successfully reco
Hikage, Shin,Sasaki, Yasuo,Hisai, Terunobu,Tanimoto, Hiroki,Morimoto, Tsumoru,Nishiyama, Yasuhiro,Kakiuchi, Kiyomi
p. 175 - 183
(2016/11/16)

Efficient and green approach for the complete deprotection of O-acetylated biomolecules
A simple, efficient and mild strategy for the complete O-deacetylation of different per-acetylated biomolecules in aqueous media has been described. Different lipases were tested but only the commercial Amano lipase A from Aspergillus Niger catalyzed the complete deprotection of peracetylated α-glucose to glucose in excellent yield. The experimental conditions were tested, in particular the pH effect. The reaction was performed at different pHs considering the only enzymatic process was evaluated at pH 5 and the combination of enzymatic and chemical migration process was evaluated at higher pHs. Finally pH 7 and 25 °C were selected as best conditions. Thus this lipase fully hydrolyzed different peracetylated α-glycopyranosides (glucose, mannose, glucal, galactal) with >99% yields, whereas very good deprotecting yields (75-80%) were achieved for different acetylated β-glycopyranosides (galactose, ribofuranose) under these mild conditions. This strategy was successfully extended to the fully O-selective deprotection of acetylated nucleosides where >99% yield was rapidly obtained. No selectivity was observed for the N-deacetylation in amino acids and peptides.
Dunne, Anthony,Palomo, Jose M.
p. 88974 - 88978
(2016/10/03)

In search of Flavivirus inhibitors part 2: Tritylated, diphenylmethylated and other alkylated nucleoside analogues
Several flaviviruses, such as the yellow fever virus and the dengue virus cause severe and potentially lethal infection in man. Following up on our initial hit 3′,5′-bistritylated uridine 1, a series of alkylated nucleoside analogues were synthesized and evaluated for their in vitro antiviral activities against dengue fever virus and yellow fever virus. Hereto, alkyl and aryl groups were attached at various positions of the sugar ring combined with subtle variation of the heterocyclic base. Among the new series of derivatives, 3′,5′-di-O-trityl-5-fluoro-2′-deoxyuridine (39) was the most efficient in this series and inhibited both yellow fever virus and dengue virus replication with a 50% effective concentration (EC50) of ～1 μg/mL without considerable cytotoxicity. The other fluorinated derivatives proved more toxic. Almost all diphenylmethylated pyrimidine nucleosides with 3′,5′-di-O-benzhydryl-2′-deoxyuridine (50) as the example were endowed with strong cytotoxic effects down to 1 μg/mL.
Saudi, Milind,Zmurko, Joanna,Kaptein, Suzanne,Rozenski, Jef,Neyts, Johan,Van Aerschot, Arthur
p. 98 - 109
(2014/03/21)

Exploring the binding of 4-thiothymidine with human serum albumin by spectroscopy, atomic force microscopy, and molecular modeling methods
The interaction of 4-thiothymidine (S4TdR) with human serum albumin (HSA) was studied by equilibrium dialysis under normal physiological conditions. In this work, the mechanism of the interaction between S 4TdR and human serum albumin (HSA) was exploited by fluorescence, UV, CD circular, and SERS spectroscopic. Fluorescence and UV spectroscopy suggest that HSA intensities are significantly decreased when adding S4TdR to HAS, and the quenching mechanism of the fluorescence is static. Also, the ΔG, ΔH, and ΔS values across temperature indicated that hydrophobic interaction was the predominant binding force. The CD circular results show that there is little change in the secondary structure of HSA except the environment of amino acid changes when adding S4TdR to HSA. The surface-enhanced Raman scattering (SERS) shows that the interaction between S4TdR and HSA can be achieved through different binding sites which are probably located in the II A and III A hydrophobic pockets of HSA which correspond to Sudlow's I and II binding sites. In addition, the molecular modeling displays that S4TdR-HSA complex is stabilized by hydrophobic forces, which result from amino acid residues. The atomic force microscopy results revealed that the single HSA molecular dimensions were larger after interaction of 4-thiothymidine. This work would be useful to understand the state of the transportation, distribution, and metabolism of the anticancer drugs in the human body, and it could provide a useful biochemistry parameter for the development of new anti-cancer drugs and research of pharmacology mechanisms.
Zhang, Juling,Gu, Huaimin,Zhang, Xiaohui
p. 102 - 111
(2014/01/17)

ANTI-CANCER AGENTS
Described herein are compounds that may be selectively activated to produce active anti-cancer agents in tumor cells. Also disclosed are pharmaceutical compositions comprising the compounds, and methods of treating cancer using the compounds.
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Paragraph 0432

(2013/03/26)

Design, synthesis, and antiviral evaluation of chimeric inhibitors of HIV reverse transcriptase
In a continuing study of potent bifunctional anti-HIV agents, we rationally designed a novel chimeric inhibitor utilizing thymidine (THY) and a TMC derivative (a diarylpyrimidine NNRTI) linked via a polymethylene linker (ALK). The nucleoside, 5′-hydrogen-phosphonate (H-phosphonate), and 5′-triphosphate forms of this chimeric inhibitor (THY-ALK-TMC) were synthesized and the antiviral activity profiles were evaluated at the enzyme and cellular level. The nucleoside triphosphate (11) and the H-phosphonate (10) derivatives inhibited RT polymerization with an IC50 value of 6.0 and 4.3 nM, respectively. Additionally, chimeric nucleoside (9) and H-phosphonate (10) derivatives reduced HIV replication in a cell-based assay with low nanomolar antiviral potencies.
Iyidogan, Pinar,Sullivan, Todd J.,Chordia, Mahendra D.,Frey, Kathleen M.,Anderson, Karen S.
supporting information
p. 1183 - 1188
(2014/01/06)

Systematic assignment of NMR spectra of 5-substituted-4-thiopyrimidine nucleosides
Unambiguous characterization of 5-substituted-4-thiopyrimidine nucleosides (ribonucleosides and 2'-deoxynucleosides) was performed using NMR spectroscopy. Assignments of all proton and carbon signals of 5-bromo-4-thiouridine and related nucleosides were systematically carried out and firmly established by COSY and HMQC techniques. The NMR data of various 4-thiopyrimidine nucleosides are compared, and the key contributing factors discussed. The approach presented here is applicable to other modified nucleosides and nucleotides, as well as nucleobases. Copyright
Zhang, Xiaohui,Wang, Jian,Xu, Yao-Zhong
p. 523 - 529
(2013/09/02)

Caged nucleotides and oligonucleotides and their application
There is disclosed nucleotides and nucleotide analogs having a protecting or “caging” group. There is further disclosed oligonucleotides and oligonucleotides analogs formed having a protecting or “caging” group. There is further disclosed a method for decaging the nucleotides and nucleotide analogs having a protecting or “caging” group and oligonucleotides and oligonucleotide analogs having a caging group.
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Page/Page column 21

(2012/08/29)

Hypoxia-selective DNA interstrand cross-link formation by two modified nucleosides
The clean crossed code: Two nitroimidazole-modified thymidines 1 a and 1 b were synthesized and incorporated into DNA oligomers. The 350 nm photolysis of 1 a and 1 b generated a 5-(2'-deoxyuridinyl)methyl radical that induced DNA interstrand cross-links (ICL; see scheme). A higher ICL yield was observed under hypoxic conditions than under aerobic conditions. Copyright
Kuang, Yunyan,Sun, Huabing,Blain, J. Craig,Peng, Xiaohua
supporting information
p. 12609 - 12613
(2012/11/14)

Semisynthetic peptide-lipase conjugates for improved biotransformations
An efficient chemoselective method for the creation of semisynthetic lipases by site-specific incorporation of tailor-made peptides on the lipase-lid site was developed. These new enzymes showed excellent improved specificity and regio- or enantioselectivity in different biotransformations.
Romero, Oscar,Filice, Marco,Guisan, Jose M.,Palomo, Jose M.,De Las Rivas, Blanca,Carrasco-Lopez, Cesar,Hermoso, Juan A.,Klett, Javier,Morreale, Antonio,Abian, Olga
supporting information
p. 9053 - 9055,3
(2020/08/31)

Synthesis of novel nucleoside 5′-triphosphates and phosphoramidites containing alkyne or amino groups for the postsynthetic functionalization of nucleic acids
A series of novel nucleoside 5′-triphosphates and phosphoramidites containing alkyne or amino groups for the postsynthetic functionalization of nucleic acids were designed and synthesized. For this purpose, the new 3-aminopropoxypropynyl linker group was used. It contains two alternative functional capabilities: an amino group for the reaction of amino-alkynyl- modified oligonucleotides with corresponding activated esters and an alkyne group for the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. It was shown that a variety of methods of the attachment of the new linker can be used to synthesize a diversity of modified pyrimidine nucleosides. Copyright Taylor and Francis Group, LLC.
Vasilyeva, Svetlana V.,Budilkin, Boris I.,Konevetz, Dmitrii A.,Silnikov, Vladimir N.
scheme or table
p. 753 - 767
(2012/07/28)

An integrated chemo-enzymatic route for preparation of β-thymidine, a key intermediate in the preparation of antiretrovirals
A chemo-enzymatic method for production of β-thymidine, an intermediate in the synthesis of antiretrovirals, is described. Guanosine and thymine were converted by means of enzymatic transglycosylation to yield 5-methyluridine (5-MU), which was reproducibly synthesised at a 10-20-L scale in 85% yield at a final product concentration of ～80 g?L-1. A downstream processing (DSP) protocol was designed to remove reaction components interfering with the subsequent synthetic step. The crystallised 5-MU produced in the biocatalytic reaction was found to behave similarly to commercially available 5-MU, and the integration of the initial biocatalytic and subsequent three-step chemical process to β-thymidine was successfully demonstrated at bench scale.
Gordon, Gregory E. R.,Bode, Moira L.,Visser, Daniel F.,Lepuru, M. Jerry,Zeevaart, Jacob G.,Ragubeer, Nasheen,Ratsaka, Molala,Brady, Dean,Walwyn, David R.
p. 258 - 265
(2011/10/04)

Facile synthesis of hydroxymethylcytosine-containing oligonucleotides and their reactivity upon osmium oxidation
DNA strands containing a 5-hydroxymethylcytosine (hmC), which have recently been found in neuron cells and embryonic stem cells, were synthesized through a facile synthetic technique. The hmC-containing strands were efficiently oxidized at hmC using an osmium oxidation assay. The hmC was oxidized as easily as 5-methylcytosine, which can be distinguished from unmethylated cytosine.
Sugizaki, Kaori,Ikeda, Shuji,Yanagisawa, Hiroyuki,Okamoto, Akimitsu
experimental part
p. 4176 - 4181
(2011/08/03)

H2SO4-SiO2: Highly efficient and reusable catalyst for per-O-acetylation of carbohydrates under solvent-free conditions
Sulfuric acid immobilized on silica gel (H2SO 4-SiO2) was used as an efficient promoter for per-O-acetylation of carbohydrates with acetic anhydride under solvent-free conditions. The substrates include not only monosaccharides and disaccharides, but also glycosides. The catalyst is recyclable and stable at room temperature, and the reaction protocol is simple, is cost-effective, and gives good isolated yield with high purity. The large-scale reactions also proceeded conveniently and in high yields. Taylor & Francis Group, LLC.
Zhang, Jianbo,Zhang, Bo,Zhou, Jiafen,Li, Juan,Shi, Chunjuan,Huang, Ting,Wang, Zhongfu,Tang, Jie
experimental part
p. 165 - 177
(2012/01/19)

An efficient deprotection of N-trimethylsilylethoxymethyl (SEM) groups from dinucleosides and dinucleotides
A convenient and efficient method for deprotection of N-(trimethyl) silylethoxymethyl (SEM) groups from thymidine dinucleoside and dinucleotide has been achieved. The SEM groups were easily removed in excellent yields from protected nucleosides, dinucleosides, and dinucleotides.
Chandra, Tilak,Broderick, William E.,Broderick, Joan B.
scheme or table
p. 132 - 143
(2011/08/05)

RNA-cleaving 10-23 deoxyribozyme with a single amino acid-like functionality operates without metal ion cofactors
A series of 10-23 deoxyribozymes (D2-D9) containing single amino-acid-bearing nucleosides (thr6dA, hisam6dA, hisam5dU and ncmnm5dU) at positions 4, 5, 8 or 15 of the catalytic core was obtained by chemical synthesis. The deoxyribozymes were screened for their catalytic efficiency, and in the presence of 1 mM Mg 2+ two of them, containing at position 8 either hisam5dU (D8) or ncmnm5dU (D9), were found to be RNA nucleases several times more active than their non-modified precursor. Moreover, in the magnesium-free TRIS or PIPES buffers, these enzymes were able to catalyze the cleavage of the phosphodiester bond located between the 5'-GpU-3' sequence of the complementary RNA substrate. The cleavage reaction proceeded with the highest efficiency at pH > 7.
Smuga, Damian,Majchrzak, Kinga,Sochacka, Elzbieta,Nawrot, Barbara
scheme or table
p. 934 - 948
(2010/08/05)

CHEMICALLY MODIFIED NUCLEOSIDE 5'-TRIPHOSPHATES FOR THERMALLY INITIATED AMPLIFICATION OF NUCLEIC ACID
Provided herein are methods and compositions for nucleic acid amplification. These methods involve the use of 3'-substituted nucleoside 5'-triphosphates or 3'-substituted terminated primers in nucleic acid amplification reactions. In certain aspects, the methods are accomplished by use of 3'-substituted NTPs and/or 3'-substituted terminated primers which provide utility in nucleic acid amplification. In preferred embodiments, the NTPs and/or primers are substituted at the 3'-position with particular heat labile chemical groups such as ethers, esters or carbonate esters.
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Page/Page column 59-60

(2010/01/07)

A versatile synthesis of 5'-fenctionalized nucleosides through regioselective enzymatic hydrolysis of their peracetylated precursors
We describe a chemo-enzymatic synthesis of modified nucleosides through lipase-catalyzed hydrolysis of their peracetylated precursors. It was found from screening of a large number of substrates that these enzymesregioselectivities were affected by the sugar and the nucleobase structures. By selecting the best enzyme for each substrate in terms of activity and regioselectivity, we prepared a small library of differently monodeprotecled purine and pyrimidine nucleosides useful as intermediates for the synthesis of high-value nucleosides and mononucleotides. By this approach, the chemo-enzymatic preparation of doxifluridine (14) and uridine 5'-monophosphate (5'-UMP, 15) from peracetylated uridine 1 was carried out. Elimination of many of the processing stages associated with existing methods was achieved, and higher yields and products of increased purity were generated. Wiley-VCH Verlag GmbH & Co. KGaA.
Bavaro, Teodora,Rocchietti, Silvia,Ubiali,Filice, Marco,Terreni, Marco,Pregnolato, Massimo
experimental part
p. 1967 - 1975
(2009/09/08)

Photochemical DNA activation
A new photocaged nucleoside was synthesized and incorporated into DNA with the use of standard synthesis conditions. This approach enabled the disruption of specific H-bonds and allowed for the analysis of their contribution to the activity of a DNAzyme. Brief Irradiation with nonphotodamaging UV light led to rapid decaging and almost quantitative restoration of DNAzyme activity. The developed strategy has the potential to find widespread application in the light-induced regulation of oligonucleotide function.
Lusic, Hrvoje,Young, Douglas D.,Lively, Mark O.,Deiters, Alexander
p. 1903 - 1906
(2008/02/04)

A pyrimidine-pyrazolone nucleoside chimera with potent in vitro anti-orthopoxvirus activity
Synthetic hybridization of two privileged drug scaffolds, pyrazolone on the one hand and pyrimidine nucleoside on the other, resulted in the generation of two novel 5-substituted pyrimidine nucleosides with potent in vitro antiviral activity against two representative orthopoxviruses, vaccinia virus and cowpox virus.
Fan, Xuesen,Zhang, Xinying,Zhou, Longhu,Keith, Kathy A.,Kern, Earl R.,Torrence, Paul F.
p. 3224 - 3228
(2007/10/03)

Transprotection of silyl ethers of nucleosides in FeCl3 based ionic liquids
Ionic liquid mediated deprotection of tert-butyldimethyl silyl (TBDMS) ethers derived from various primary and secondary alcohols have been studied and the reaction conditions optimized. Deprotection of the silyl ethers in FeCl3 based ionic liquids in presence of acetic anhydride yielded the acetate esters of the corresponding alcohols in good yields. The transprotection methodology was extended to the silyl ethers of nucleosides to yield the corresponding acetylated products. Copyright Taylor & Francis, Inc.
Harjani, Jitendra R.,Nara, Susheel J.,Salunkhe, Manikrao M.,Sanghvi, Yogesh S.
p. 819 - 822
(2007/10/03)

A new synthetic analogue of thymidine, 7-(3-bromo-phenoxy)-thymidine, inhibits the proliferation of tumor cells
The synthesis of new thymidine analogues and their biological activities are described. Modified thymidine analogues have been highlighted as useful agents for the treatment of cancer and viral diseases due to their potent biological activities. In the present study, we synthesized a new thymidine analogue, 7-(3-bromo-phenoxy)-thymidine (4a), as a potential lead for anti-tumor agent. Compound 4a potently inhibits HeLa cell proliferation with an IC 50 of 15 μM.
Kim, Kyung Noo,Lee, Jiyong,Kim, Dong Hoon,Yoo, Jong-Shin,Kwon, Ho Jeong
p. 77 - 79
(2007/10/03)

Acetonyltriphenylphosphonium bromide (ATPB): A versatile reagent for the acylation of alcohols, phenols, thiols and amines and for 1,1-diacylation of aldehydes under solvent-free conditions
A wide variety of alcohols, phenols, amines and thiols may easily be converted into the corresponding acetate derivatives by treatment with acetic anhydride (1.5-2.0 equivalents) in the presence of acetonyltriphenylphosphonium bromide (ATPB; 5 mol %) in good yields at room temperature. With the same precatalyst, both aliphatic and aromatic aldehydes can also be transformed into the corresponding gemdiacetates under reflux conditions.
Khan, Abu T.,Choudhury, Lokman H.,Ghosh, Subrata
p. 2782 - 2787
(2007/10/03)

A zero-length diazirine photoactive nucleoside
The scheme of synthesis which allows to obtain 5-(3H-diazirin-3-yl)-2′-deoxyuridine as the zero-length photoactive nucleoside is described.
Taranenko,Mtchedlidze,Sumbatyan,Korshunova
p. 715 - 717
(2007/10/03)

A New Method for the Preparation of Modified Oligonucleotides
(Equation Presented) N-Nitrothymidine can be transformed into a phosphoramidite building block suitable for oligonucleotide synthesis using the standard phosphite triester solid-phase approach. The N-nitrothymidine residues remain stable during the elongation cycles and react smoothly with primary amines, furnishing oligonucleotides containing N3-modified thymidines. A number of N3-substituted oligonucleotides have been prepared using this methodology, some of them incorporating aminoalkyl or hydroxyalkyl groups.
Gorchs, Olga,Hernandez, Marta,Garriga, Lourdes,Pedroso, Enrique,Grandas, Anna,Farras, Jaume
p. 1827 - 1830
(2007/10/03)

Unexpected shift to a 4-imino tautomer upon N4-acylation of 5- methylcytosin-1-yl nucleoside analogues
In contrast with the behaviour of 5-unsubstituted cytosine nucleoside analogues, 5-methylcytosine derivatives show upon N4-benzoylation, commonly used as base protection in oligonucleotide synthesis, a tautomeric change of the base moiety from a 4-amino- into a 4-imino isomer. In the latter form, which is easily diagnosticized by 13C NMR and confirmed by X-ray data, the compounds seem to be hydrolytically less stable.
Busson,Kerremans,Van Aerschot,Peeters,Blaton,Herdewijn
p. 1079 - 1082
(2007/10/03)

Synthesis of prodrugs as bridged nucleosides
Methods for the preparation of N, N'-connected bisnucleosides have been developed. The bridge is formally a carbonate ester of N-hydroxymethyl nucleosides. Both symmetrical and non-symmetrical bridged bisnucleosides are available. Acta Chemica Scandinavica 1998.
Hatlelid, Jostein,Benneche, Tore,Undheim, Kjell
p. 1270 - 1274
(2007/10/03)

Synthesis of 5-methyl-2'-O-deoxycytidine analogs to determine monoclonal antibody specificity in the recognition of the 6-(p-bromobenzoylamino) caproyl radical
Eight new p-bromobenzoyl derivatives of 5-methyl-2'-O-deoxycytidine analogs, substituted at the 4-position, were synthesized. The best conditions for obtaining 5-methyl-4-N-aminoalkyl-2'-O-deoxycytidine from 3',5'-di-O- acetyl-4-(1,2,4-triazol-1-yl)-2'-O-deoxythymidine were studied. The nucleoside analogs were used to identify the fragment of the 6-(p- bromobenzoylamino)caproyl radical that binds to the monoclonal antibody obtained against it and to define an affinity scale of monoclonal antibody against them.
Rodriguez-Tanty,Higginson-Clarke,Hernandez,Perez,Velez- Castro,Riveron,Macias
p. 455 - 467
(2007/10/03)

Ozonation of thionucleosides. A new chemical transformation of 4-thiouracil and 6-thioguanine nucleosides to cytosine and adenosine counterparts
The ozonation of 4-thiopyrimidine and 6-thiopurine nucleosides in presence of amines afforded selectively and under mild experimental conditions several cytidine and adenosine nucleosides. The same reaction carried out in presence of alcohols afforded O4- or O6-alkylated derivatives of the nucleosides.
Saladino, Raffaele,Crestini, Claudia,Occhionero, Francesca,Nicoletti, Rosario
p. 3607 - 3616
(2007/10/02)

Differential reactivity of carbohydrate hydroxyls in glycosylations. II. The likely role of intramolecular hydrogen bonding on glycosylation reactions. Galactosylation of nucleoside 5'-hydroxyls for the syntheses of novel potential anticancer agents
Contrary to expectations, many primary hydroxy groups are completely unreactive in glycosylation reactions, or give the desired glycosides in very low yields accompanied by products of many side reactions. Hydrogens of such primary hydroxyls are shown to be intramolecularly hydrogen bonded. Intermediates formed by nucleophilic attack by these hydroxyls on activated glycosylating agents may resist hydrogen abstraction. This resistance to proton loss is postulated to be the origin of the observed unreactivity. It is shown that successful glycosylations take place under acidic conditions under which such hydrogen bonds cease to exist. Accordingly, direct galactosylations of the normally unreactive 5'-hydroxyls of nucleosides were accomplished for the first time with a galactose trichloroacetimidate donor in chloroform under silver triflate promotion. It is noted that such galactosylated anticancer nucleosides may have improved biological specificity. Contrary to expectations, many primary hydroxy groups are completely unreactive in glycosylation reactions, or give the desired glycosides in very low yields accompanied by products of many side reactions. Hydrogens of such primary hydroxyls are shown to be intramolecularly hydrogen bonded. Intermediates formed by nucleophilic attack by these hydroxyls on activated glycosylating agents may resist hydrogen abstraction. This resistance to proton loss is postulated to be the origin of the observed unreactivity. It is shown that successful glycosylations take place under acidic conditions under which such hydrogen bonds cease to exist. Accordingly, direct galactosylations of the normally unreactive 5′-hydroxyls of nucleosides were accomplished for the first time with a galactose trichloroacetimidate donor in chloroform under silver triflate promotion. It is noted that such galactosylated anticancer nucleosides may have improved biological specificity.
Whitfield,Douglas,Tang,Csizmadia,Pang,Moolten,Krepinsky
p. 2225 - 2238
(2007/10/02)

Photocycloaddition of deoxyuridines to 2,3-dimethyl-2-butene
Direct and ketone (acetone or acetophenone)-sensitized photocycloaddition of 2,3-dimethyl-2-butene fo 2'-deoxyuridine (1a), thymidine (1b), 5-fluoro-2'-deoxyuridine (1c), and their 3',5'-di- O-acetyl derivatives 1d-1f by near-UV irradiation have been studied. The triplet excited state of the nucleosides was found to be the major intermediate by the triplet quenching technique. From the respective reactants, a pair of diastereomeric products having a cyclobutane ring were isolated. The absolute configuration of the bridgehead carbon atoms was identified by X-ray crystallographic analyses with two of them as (1R, 6R)-isomer 3a and (1S, 6S)-isomer 2b and by 1H NMH. The conformations of the glycosyl bond, the pyrimidine ring, and the sugar portion in solution were identified by 1H NMR and compared with the ones in the crystalline state.
Haga,Ishikawa,Takayanagi,Ogura
p. 728 - 737
(2007/10/02)

Eine kurze Synthese von -3'-Azido-3'-desoxythymidin (N3-markiertes AZT) ueber 3-Nitro-AZT
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Ariza, Xavier,Bou, Valenti,Vilarrasa, Jaume,Tereshko, Valya,Campos, J. Lourdes
p. 2535 - 2537
(2007/10/02)

Solid-phase synthesis of oligonucleotides containing 4-alkoxythymidine residues
Immobilized and fully protected oligodeoxynucleotides containing a 4-(1,2,4-triazolyl)thymidine residue at a predetermined position were prepared according to a well-established phosphite triester methodology using 2-cyanoethyl phosphoramidites of a 4-(1,2,4-triazolyl)-substituted thymidine and standard protected nucleosides.Treatment of the immobilized oligomer with methanol, ethanol or n-propanol in the presence of DBU at 50 deg C gave the corresponding oligonucleotides containing 4-methoxy, 4-ethoxy or 4-n-propoxythymidine residue.
Roelen, H. C. P. F.,Brugghe, H. F.,Elst, H. van den,Marel, G. A. van der,Boom, J. H. van
p. 99 - 104
(2007/10/02)

Conformational Transmission in Nucleotides Containing Trigonal Bipyramidal Phosphorus as the Internucleoside Linkage
A set of nucleotide analogues containing a stable trigonal bipyramidal phosphorus (PV TBP) moiety (5-11) has been developed, and their conformational properties were studied with 300- and 500-MHz 1H NMR.In the solvent acetone-d6, it is found that the conformation of the model compounds is determined by a hydrogen bond between the backbone atom O5', and the base proton H6 (pyrimidine base) or H8 (purine base), resulting in a preference for the standard gauche(+) conformation around the C4'-C5' bond.In the hydrogen bond disrupting solvent DMSO-d6, the PV TBP nucleotides 5-8 clearly show conformational transmission, i.e., a preference for the unusual gauche(-) (g-) rotamer around the C4'-C5' bond is found.This structural distortion opposes stacking of the bases, as is confirmed by the observation that the preference for g- is strongest for 7 and 8, in which stacking is eliminated.The present results provide support to our earlier proposition that formation of PV TBP locations in DNA can lead to a marked change of the secondary structure (Buck, H.M.Recl.Trav.Chim.Pays-Bas 1980, 99, 181).
Koole, Leo H.,Genderen, Marcel H. P. van,Buck, Henk M.
p. 5266 - 5272
(2007/10/02)

A Parallel Right-Handed Duplex of the Hexamer d(TpTpTpTpTpT) with Phosphate Triester Linkeges
We show in this work that stable parallel thymine-thymine (T-T) base pairs can be formed in aqueous solution.Initially, this observation was made with 3',5'-di-O-acetylthymidine in water which showed an imino resonance at 13.45 ppm in the 1H NMR spectrum.Using the nucleoside diphosphate d(pTp), the formation of T-T base pairs could only be induced via methylation of the phosphate groups.This leads to the suggestion that intramolecular electrostatic phosphate-phosphate repulsion preludes T-T base pairing for unmodified d(pTp).It is shown that T-T pairing is also manifest on the dinucleotide level, provided that the phosphate groups are methylated.Using the dinucleoside phosphate 1 which was separated in its diastereomeric forms, it was shown that the miniduplex melts at Tm ca. 30 deg C.Furthermore, it was shown that the duplex of 1 is parallel.From the detailed conformational analysis of the individual diastereomers it follows that the duplex has a right-handed helical sense, since the backbone bonds C4'-C5' and C5'-O5' are preferentially γ+ and βt, and the furanoses reside primarily in the south conformation.With the hexamer d(TpTpTpTpTpTp), it was shown that T-T pairing also occurs on the hexanucleotide level, after methylation of the phosphate groups.The resulting duplex has a Tm value of approximately 65 deg C as was established with UV hyperchromicity and with variable-temperature 500-MHz 1H NMR.It could be clearly established that the duplex is parallel.Molecular modelling studies on the duplex of phosphate-methylated d(TpTpTpTpTpT) yielded a remarkably slim, parallel structure with about eight residues per turn.The possible relevance of these alternative DNA-like duplexes is briefly mentioned.
Koole, Leo H.,Genderen, Marcel H. P. van,Buck, Hendrik K.
p. 3916 - 3921
(2007/10/02)

SYNTHETIC ROUTE TO 5-SUBSTITUTED URIDINES VIA A NEW TYPE OF DESULFURIZATIVE STANNYLATION
Phenylthio group at the C-6 position of uridine serves as the protecting group during lithiation at the C-5 position with lithium 2,2,6,6-tetramethylpiperidine.Reactions of the resulting C-5 lithiated species with various types of electrophiles furnish 5-substituted 6-phenylthiouridine derivatives.The phenylthio group in these products can be removed by a new type of desulfurizative stannylation with tributyltin hydride followed by protonolysis.The whole sequence constitutes a new route to 5-substituted uridines.Application of this method to 2'-deoxyuridine is also described.
Tanaka, Hiromichi,Hayakawa, Hiroyuki,Obi, Kikoh,Miyasaka, Tadashi
p. 4187 - 4196
(2007/10/02)

The Protection of Thymine and Guanine Residues in Oligodeoxyribonucleotide Synthesis
Thymidine is converted in four steps into its crystalline 4-O-phenyl derivative (14b) in 72percent overall yield. 2'-Deoxyguanosine is converted in five steps into its 6-O-(2-nitrophenyl)-2-N-phenylacetyl and crystalline 6-O-(3,5-dichlorophenyl)-2-N-phenylacetyl derivatives in ca. 39 and 42percent overall yields, respectively.Compounds (14b), (19a), and (19b) are converted into the corresponding crystalline 5'-O-(9-phenyl-9H-xanthen-9-yl) derivatives (15), (20a), and (20b), respectively.The actions of N1,N1,N3,N3-tetramethylguanidinium 2-nitrobenzaldehyde oximate, 80percent acetic acid, potassium carbonate in aqueous dioxane, pyridine, and triethylammonium toluene-p-thiolate on (14b), (19a), and (19b) have been investigated.
Reese, Colin B.,Skone, Philip A.
p. 1263 - 1271
(2007/10/02)

Two New Protected Acyl Protecting Groups for Alcoholic Hydroxy Functions
4-(Methylthiomethoxy)butyric acid (13a) and 2-(methylthiomethoxymethyl)benzoic acid (14a) have been prepared in 53 and 64percent overall yields from γ-butyrolactone and phthalide, respectively.Thymidine reacts regioselectively with (13a) and (14a), in the presence of an appropriate condensing agent, to give the corresponding 5'-O-acyl derivatives , both in 70percent yield.The latter compounds undergo deacylation relatively slowly when treated with concentrated aqueous ammonia, but following treatment with mercury(II) perchlorate in the presence of 2,4,6-collidine in slightly wet tetrahydrofuran, are both converted back into thymidine under very mild conditions of basic hydrolysis.
Brown, Jonathan M.,Christodoulou, Chris,Reese, Colin B.,Sindona, Giovanni
p. 1785 - 1790
(2007/10/02)

Biologically active glycosides from asteroidea, I. - Structures of a new cerebroside mixture and of two nucleosides from the starfish Acanthaster planci
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Komori,Sanechika,Ito,et al.
p. 653 - 668
(2007/10/02)