- Hydrogen-bonding linkage of thymidine derivatives with carboxylic acid and pyridyl groups in a crystalline state
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Thymidine derivatives with carboxylic acid and pyridyl groups were synthesized for constructing one-dimensional network structure based on hydrogen bonding in crystalline state. The solid sate structures and hydrogen bonding networks of the thymidine derivatives were characterized by single X-ray diffraction analysis. The thymidine derivatives formed a zwitterion structure with a pyridinium proton and a carboxylate moiety in a crystalline state due to transfer of a proton from the carboxylic acid to the pyridyl moiety. Strong hydrogen bonds between the pyridinium proton and the carboxylate moiety connected the thymidine units, resulting in a one-dimensional polymeric structure with a uniform direction reminiscent of the structure of single-strand polythymidine. The chemical structure of the pyridyl group affects the hydrogen-bonding networks. The well-designed hydrogen-bonding interaction served as connecting parts for polythymidine mimics even in the presence of other hydrogen-bonding motifs such as nucleobases. Copyright
- Hoshino, Junichi,Kuwabara, Junpei,Kanbara, Takaki
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Read Online
- The cleavage of the 2,2,2-trichloro-1,1-dimethylethoxycarbonyl protective group by tin(II) tris(benzenethiolate)
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The cleavage of the 2,2,2-trichloro-1,1-dimethylethoxycarbonyl (trichloro-tert-butoxycarbonyl, TCBOC) protective group for amino and hydroxy functions by tin(II) tris[benzenethiolate] in the presence of tetrabutylammonium cobalt(II) phthalocyanine-5,12,19,26-tetrasulfonate is reported. This combination is superior to previously used deblocking reagents for the TCBOC-group.
- Lehnhoff,Karl,Ugi
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Read Online
- Synthesis of Ribonucleosidic Dimers with an Amide Linkage from D-Xylose
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An original and efficient stereocontrolled synthesis of ribonucleosidic homo- and heterodimers has been achieved from inexpensive d-xylose. This successful strategy involved the sequential introduction of nucleobases, using two stereocontrolled N-glycosidation reactions, from a common two-furanoside amide-linked scaffold offering the possibility of obtaining any given base sequence. The pertinence of this approach is illustrated through the preparation of the homodimers UU-34 and TT-35 in 18 steps with an excellent overall yield of more than 10% from d-xylose, while the heterodimer route led to UT-39 in 19 steps with around 10% overall yield.
- Arzel, Laurence,Dubreuil, Didier,Dénès, Fabrice,Silvestre, Virginie,Mathé-Allainmat, Monique,Lebreton, Jacques
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p. 10742 - 10758
(2016/11/29)
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- Anti-flavivirus Activity of Different Tritylated Pyrimidine and Purine Nucleoside Analogues
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A series of tritylated and dimethoxytritylated analogues of selected pyrimidine and purine nucleosides were synthesized and evaluated for their in vitro inhibitory activity against two important members of the genus Flavivirus in the Flaviviridae family, the yellow fever (YFV) and dengue viruses (DENV). Among all compounds tested, the 5′-O-tritylated and the 5′-O-dimethoxytritylated 5-fluorouridine derivatives exerted potency against YFV. Interestingly in the series of purine analogues, the 5′O, N-bis-tritylated fludarabine derivative revealed strong inhibitory activity against DENV at μm concentrations, however significantly weaker potency against YFV.
- McGuigan, Christopher,Serpi, Michaela,Slusarczyk, Magdalena,Ferrari, Valentina,Pertusati, Fabrizio,Meneghesso, Silvia,Derudas, Marco,Farleigh, Laura,Zanetta, Paola,Bugert, Joachim
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p. 227 - 235
(2016/07/07)
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- Optimized synthesis of 3′-O-aminothymidine and evaluation of its oxime derivative as an anti-HIV agent
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The synthesis and isolation of 3′-O-aminothymidine oximes have been optimized. Synthesized compounds were characterized by NMR and UV spectral and analytical data. A mixture of previously not reported syn and anti isomers of acetaldoximes was assessed for anti-HIV activity and the prevention of syncytia formation caused by HIV-1 infection.
- Solyev, Pavel N.,Jasko, Maxim V.,Martynova, Tatiana A.,Kalnina, Ludmila B.,Nosik, Dmitry N.,Kukhanova, Marina K.
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p. 291 - 295
(2015/10/28)
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- In search of Flavivirus inhibitors part 2: Tritylated, diphenylmethylated and other alkylated nucleoside analogues
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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
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- In search of flavivirus inhibitors: Evaluation of different tritylated nucleoside analogues
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Following up on a hit that was identified in a large scale cell-based antiviral screening effort, a series of triphenylmethyl alkylated nucleoside analogues were synthesized and evaluated for their in vitro antiviral activities against the dengue virus (DENV) and the yellow fever virus (YFV). Hereto, trityl moieties were attached at various positions of the sugar ring combined with subtle variations of the heterocyclic base. Several triphenylmethyl modified nucleosides were uncovered being endowed with submicromolar in vitro antiviral activity against the YFV. The most selective inhibitor in this series was 3′,5′-bis-O-tritylated-5-chlorouridine (1b) affording a selectivity index of over 90, whereas the 3′,5′-bis-O-tritylated inosine congener (5b) displayed the highest activity, but proved more toxic. The finding of these lipophilic structures being endowed with high antiviral activity for flaviviruses, should stimulate the interest for further structureeactivity research.
- Chatelain, Grégory,Debing, Yannick,De Burghgraeve, Tine,Zmurko, Joanna,Saudi, Milind,Rozenski, Jef,Neyts, Johan,Van Aerschot, Arthur
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supporting information
p. 249 - 255
(2013/10/01)
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- Synthesis of new pyrimidine nucleoside derivatives with nitric oxide donors for antiviral activity
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New pyrimidine nucleoside derivatives with nitric oxide (NO) donor were systematically synthesized. The antivirus activities of these nucleoside analogues against vesicular stomatitis virus (VSV) in Wish cell were evaluated. It was demonstrated that most of compounds had stronger antiviral acitivity than acyclovir, while their toxicities were similar or lower to acyclovir.
- Shi, Jing Bo,Xu, Song,Wang, Ya Ping,Li, Jing Jing,Yao, Qi Zheng
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scheme or table
p. 899 - 902
(2012/01/11)
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- Nucleoside and nucleotide analogues by catalyst free Huisgen nitrile oxide-alkyne 1,3-dipolar cycloaddition
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An efficient, catalyst free, 1,3-dipolar cycloaddition strategy to conjugate nucleosides and nucleotides with isoxazoles under atmospheric conditions and in an aqueous environment is reported. The protocol involves chloramine-T as a practical reagent to induce in situ nitrile oxide formation and the alkyne partner is attached to the sugar residue or the nucleobase. The reactions are regiospecific, fast and high yielding.
- Algay, Virginie,Singh, Ishwar,Heaney, Frances
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scheme or table
p. 391 - 397
(2010/02/15)
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- 3′-Bromo analogues of pyrimidine nucleosides as a new class of potent inhibitors of mycobacterium tuberculosis
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Tuberculosis (TB) is a major health problem worldwide. We herein report a new class of pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis (M. tuberculosis). Various 2′- or 3′-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases were synthesized and evaluated for antimycobacterial activities. Among the compounds tested, 3′-bromo-3′-deoxy- arabinofuranosylthymine (33) was the most effective antituberculosis agent in the in vitro assays against wild-type M. tuberculosis strain (H37Ra) (MIC 50 = 1 μg/mL) as well as drug-resistant (H37Rv) (rifampicin-resistant and isoniazid-resistant) strains of M. tuberculosis (MIC50 = 1-2 μg/mL). Compound 33 also inhibited intracellular M. tuberculosis in a human monocytic cell line infected with H37Ra, demonstrating higher activity against intramacrophagic mycobacteria (80% reduction at 10 μg/mL concentration) than extracellular mycobacteria (75% reduction at 10 μg/mL concentration). In contrast, pyrimidine nucleosides possessing 5-fluorouracil base were weak inhibitors of M. tuberculosis. No cytotoxicity was found up to the highest concentration of compounds tested (CC50 > 100-200 μg/mL) against a human cell line. Overall, these encouraging results substantiate the potential of this new class of compounds as promising antituberculosis agents.
- Shakya, Neeraj,Srivastav, Naveen C.,Desroches, Nancy,Agrawal, Babita,Kunimoto, Dennis Y.,Kumar, Rakesh
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experimental part
p. 4130 - 4140
(2010/09/04)
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- Antiviral activity of various 1-(2′-Deoxy-β- d -lyxofuranosyl), 1-(2′-Fluoro-β- d -xylofuranosyl), 1-(3′-Fluoro-β- d -arabinofuranosyl), and 2′-fluoro-2′,3′-didehydro-2′, 3′-dideoxyribose pyrimidine nucleoside analogues against duck hepatitis B virus (DHBV) and human hepatitis B virus (HBV) replication
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Despite the existence of successful vaccine and antiviral therapies, infection with hepatitis B virus (HBV) continues to be a major global cause of acute and chronic liver disease and high mortality. We synthesized and evaluated several lyxofuranosyl, 2′-fluoroxylofuranosyl, 3′- fluoroarabinofuranosyl, and 2′-fluoro-2′,3′-didehydro- 2′,3′-dideoxyribose pyrimidine nucleoside analogues for antiviral activities against hepatitis B virus. Among the compounds examined, 1-(2-deoxy-β-d-lyxofuranosyl)thymine (23), 1-(2-deoxy-β-d- lyxofuranosyl)-5-trifluoromethyluracil (25), 1-(2-deoxy-2-fluoro-β-d- xylofuranosyl)uracil (38), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)thymine (39), 2′,3′-dideoxy-2′,3′-didehydro-2′- fluorothymidine (48), and 2′,3′-dideoxy-2′,3′-didehydro- 2′-fluoro-5-ethyluridine (49) were found to possess significant anti-HBV activity against DHBV in primary duck hepatocytes with EC50 values of 4.1, 3.3, 40.6, 3.8, 0.2, and 39.0 μM, respectively. Compounds 23, 25, 39, 48, and 49 (EC50 = 41.3, 33.7, 19.2, 2.0-4.1, and 39.0 μM, respectively) exhibited significant activity against wild-type human HBV in 2.2.15 cells. Intriguingly, 25, 39, 48, and 49 retained sensitivity against lamivudine-resistant HBV containing a single mutation (M204I) and 48 emerged as an effective inhibitor of drug-resistant HBV with an EC50 of 4.1 μM. In contrast, 50% inhibition could not be achieved by lamivudine at 44 μM concentration in the drug-resistant strain. The compounds investigated did not show cytotoxicity to host cells up to the highest concentrations tested.
- Srivastav, Naveen C.,Shakya, Neeraj,Mak, Michelle,Agrawal, Babita,Tyrrell, D. Lorne,Kumar, Rakesh
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experimental part
p. 7156 - 7166
(2010/12/19)
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- Method for sequencing DNA and RNA by synthesis
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This invention relates to the field of nucleic acid chemistry, more specifically to the field of compositions and processes that are nucleic acid analogs. More specifically, this invention relates to compositions that allow the sequencing of oligonucleotides by synthesis, and processes for sequencing by synthesis that exploit these compositions. Most specifically, the instant invention discloses compositions of matter that are 5′-triphosphates of ribo- and 2′-deoxyribonucleosides wherein the 3′-OH group is replaced by a 3′-ONHR group in the alpha configuration, wherein R is either a H or CH3 group. Also disclosed are these triphosphates where the nucleobase carries, via a linker, a reporter groups, such as a fluorescent species that can be used in single- or multi-copy DNA sequencing, or a tag that can be visualized by ultramicroscopy. Also disclosed are processes that use these compositions to do sequencing by synthesis.
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Page/Page column 12
(2009/06/27)
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- Exploring the potential of 3′-O-carboxy esters of thymidine as inhibitors of ribonuclease A and angiogenin
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In this study, compounds with a carboxy ester in lieu of the phosphate ester at the 3′-position have been employed to inhibit the ribonucleolytic activity of ribonuclease A (RNase A). Phosphates at the 3′-position of pyrimidine bases are well-known inhibitors of the protein. We have investigated the inhibition of RNase A by 3′-O-carboxy esters of thymidine. The compounds behave as competitive inhibitors with inhibition constants ranging from 42 to 95 μM. The mode of inhibition has also been confirmed by 1H NMR studies of the active site histidines of RNase A. Docking studies have further substantiated the experimental results. The compounds are also found to inhibit the ribonucleolytic activity of angiogenin, a homologous protein and potent inducer of blood vessel formation.
- Ghosh, Kalyan S.,Debnath, Joy,Dutta, Palash,Sahoo, Bijaya K.,Dasgupta, Swagata
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p. 2819 - 2828
(2008/09/20)
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- Synthesis and application of a 5′-aldehyde phosphoramidite for covalent attachment of DNA to biomolecules
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We recently reported the use of covalently attached DNA as a structural constraint for rational control of macromolecular conformation. Reductive amination was employed to attach each strand of the duplex DNA constraint to RNA, utilizing an aldehyde tethered to the 5′-terminus of the DNA. Here we describe the synthesis of a thymidine phosphoramidite that has the 5′-tethered aldehyde masked as a 1,2-diol. We also describe optimized reductive amination conditions for linking 5′-aldehyde-DNA with 2′-amino-2′-deoxy-RNA. These procedures should be generally applicable for attaching DNA to biomolecules.
- Miduturu, Chandrasekhar V.,Silverman, Scott K.
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p. 5774 - 5777
(2007/10/03)
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- Synthesis of beta-L-2'-deoxy nucleosides
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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 43
(2010/02/11)
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- NUCLEOSIDE ANALOGUES WHOSE SUGAR MOIETIES ARE BOUND IN S-FORM AND OLIGONUCLEOTIDE DERIVATIVES COMPRISING NUCLEOTIDE ANALOGUES THEREOF
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Compounds of the following general formula (1) and salts thereof: where A represents an alkylene group having 1 to 2 carbon atoms, etc.; B represents an aromatic heterocyclic group which may have a substituent, etc.; R1 and R2 each represent a hydrogen atom, a protective group for a hydroxyl group for synthesis of nucleic acid, a phosphate group, or -P(R4)R5 [where R4 and R5 are the same or different, and each represent a hydroxyl group, a hydroxyl group protected with a protective group for synthesis of nucleic acid, a mercapto group, a mercapto group protected with a protective group for synthesis of nucleic acid, etc.]; and R3 represents a hydrogen atom, a halogen atom, a hydroxyl group, a hydroxyl group protected with a protective group for synthesis of nucleic acid, etc. These compounds are useful for producing oligonucleotide analogues useful for the antisense method, antigene method, etc., and for producing their intermediates.
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Page 27; 28; 29
(2010/02/09)
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- Labelling compounds for the simple synthesis of 3'-(18f)fluoro-3'-deoxy thymidine and a method for the production thereof
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The application relates to compounds that are suitable as labelable precursors for synthesis of 3′-[18F]fluoro-3′-deoxythymidine and that have formula (1), 1in which R denotes triphenylmethyl, triphenylmethyl substituted in the phenyl group, trialkylmethyl, triphenylsilyl, triphenylsilyl substituted in the phenyl group, or trialkylsilyl, R′ denotes R1—SO2, where R1 is an unsubstituted or substituted C1 to C5 alkyl or an unsubstituted or substituted phenyl, and R″ denotes C2 to C10 alkyloxycarbonyl, with the exception of 3-N-Boc-1-(3-O-nosyl-5-O-trityl-2-deoxy-β-D-lyxofuranosyl)thymine. The application also relates to a method for preparation of these compounds and to the use of the same for synthesis of 3′-[18F]fluoro-3′-deoxythymidine.
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- New and efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides
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A short, efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides 1 has been developed through the diastereoselective addition of methylmagnesium bromide or methyllithium to an intermediate tert-butylsulfinimide.
- Jung, Pierre M. J.,Beaudegnies, Renaud,De Mesmaeker, Alain,Wendeborn, Sebastian
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p. 293 - 297
(2007/10/03)
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- Synthesis and characterisation of novel 3′-O- and 5′-O- modified azobenzene-thymidine phosphoramidites and their oligonucleotide conjugates as colorimeter DNA probes and FRET quenchers
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The synthesis of two new 'first generation' azobenzene based thymidine phosphoramidites 1 and 2 having the chromophore (DABCYL) covalently incorporated as an ester in the 3′-O- and 5′-O-positions of the deoxyribose, and the incorporation of these molecules into 16-mer Chronic Myeloid Leukaemia (CML) antisense oligonucleotides, giving 7 and 8, respectively, is described. These compounds were designed as highly coloured probes, and to participate in a Fluorescence Resonance Energy Transfer (FRET) mechanism in the design of novel molecular beacons.
- Gunnlaugsson, Thorfinnur,Kelly, John M.,Nieuwenhuyzen, Mark,O'Brien, Aoife M.K.
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p. 8571 - 8575
(2007/10/03)
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- A facile one-pot synthesis of 2,3'-anhydro-2'-deoxyuridines via 3'-O-imidazolylsulfonates
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Continued interests in the novel synthetic methods of the pivotal compound, 2,3'-anhydro-2'-deoxyribonucleosides (7) uncovered a facile one-pot conversion of 5 with 1,1'-sulfonyldiimidazole in basic conditions to 7 with almost quantitative yields (91-99%).
- No,Dong Seong Shin,Bok Ju Song,Ahn,Ha
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p. 3873 - 3882
(2007/10/03)
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- Synthesis of novel carbazoyl linked pyrimidine-pyrimidine and pyrimidine-purine dinucleotide analogues
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The synthesis of two backbone modified dinucleotide analogues is described in which the natural phosphodiester linkage is replaced by a 3'-5' carbazoyl linkage. In both cases the bridge was formed through a coupling reaction between an appropriate 3'-carbazoyl nucleoside analogue and an aldehyde nucleoside derivative. It is noteworthy that starting nucleosides 4 could be common materials to obtain the 3'-carbazoyl nucleoside derivatives 2, by means of a simple, previously-described chemoenzymatic procedure, and the aldehyde nucleoside 3, by an oxidation reaction.
- Magdalena, Julia,Fernandez, Susana,Ferrero, Miguel,Gotor, Vicente
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p. 1787 - 1790
(2007/10/03)
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- Synthesis of pyrimidine 2'3'-dideoxy-2-thionucleosides
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2'-Deoxyuridine 8a and thymidine 8b were converted in eight steps and in satisfactory overall yields into 2',3'-dideoxy-2-thiouridine (ddTU) 6a and 3'-deoxy-2-thiothymidine (ddTT) 6b, respectively. A three-step procedure is described for the conversion of ddTU 6a and ddTT 6b into the corresponding 2',3'-dideoxycytidine derivatives (ddTC 7a and ddMTC 7b, respectively) in good overall yield.
- Joshi,Reese,Varaprasad
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p. 209 - 218
(2007/10/02)
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- Synthesis and Biological Evaluation of 5-Fluoro-2'-deoxyuridine Phosphoramidate Analogs
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A series of alkylating phosphoroamidate analogs of 5-fluoro-2'-deoxyuridine has been prepared and their growth inhibitory activity evaluated against murine L1210 leukemia and B16 melanoma cells in vitro.These compounds were designed to undergo intracellular release of the phosphoramidate anions, which it was hoped would function as irreversible inhibitors of thymidylate synthase.The expectation was that binding of the nucleoside moiety would be followed by alkylation of the enzyme via the phosphoramidate.The chloride, bromide, iodide, and tosylate analogs were highlypotent inhibitors of L1210 cell proliferation, with increased inhibition observed at both higher drug concentrations and longer exposure times.Addition of thymidine completely reversed the inhibition for all compounds, suggesting that these compounds are acting via inhibition of thymidylate synthase.Although the nonalkylating morpholine analog 1f was ca. 50-fold less potent than the methyl(chloroethyl)amino compound, the piperidine analog 1g was only 2-fold less potent, confirming that nitrogen basicity may be as important as the presence of an alkylating group.Addition of thymidine reversed the growth inhibition of the morpholine and piperidine analogs, suggesting that these compounds may also undergo intracellular conversion to 5-fluoro-2'-deoxyuridine 5'-monophosphate.The thymidine and deoxyuridine derivatives 2 and 3 showed minimal growth inhibition in the L1210 assay.The alkylating analogs showed modest cytotoxicity against B16 melanoma cells, and the potency of the analogs was more dependent upon the alkylating moiety than on the 5-substituent.
- Fries, Kristin M.,Joswig, Carolyn,Borch, Richard F.
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p. 2672 - 2680
(2007/10/03)
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- Synthesis of a new hydroxyamino linked thymidine dimer via a radical C-C bond formation
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An efficient synthesis of a thymidine nucleoside dimer [T-3'-β-O- N(CH3)-CH2-5'-T] has been accomplished via an intermolecular radical coupling reaction. The novel dimer contains an achiral and neutral backbone linkage which may have potential application in constructing backbone modified antisense oligonucleosides.
- Sanghvi,Cook
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p. 859 - 862
(2007/10/02)
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- Novel 6-alkoxypurine 2',3'-dideoxynucleosides as inhibitors of the cytopathic effect of the human immunodeficiency virus
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Twenty-one 6-alkoxypurine 2',3'-dideoxynucleosides were enzymatically synthesized with nucleoside phosphorylases purified from E. coli. Eighteen analogs exhibited anti-HIV-1 activity in MT4 cells. Two analogs, 6- (hexyloxy)- (17) and 6-(heptyloxy)- (18) purine 2',3'-dideoxynucleoside, were as potent as 2',3'-dideoxyinosine (ddI, didanosine, Videx). Although the antiviral activities of 17 and 18 were equivalent, 18 was more cytotoxic. Analogs containing less than four carbons in the 6-alkoxypurine substituent exhibited weak anti-HIV-1 activity. Analogs containing more than seven carbons in the 6-alkoxypurine substituent were too cytotoxic to be effectively evaluated for antiviral activity. Several 6-alkoxypurine 2',3'- dideoxynucleosides were evaluated for substrate activity with calf intestinal adenosine deaminase (ADA). Increasing the carbon chain length of the 6- alkoxypurine substituent decreased the rate of dealkoxylation. The best substrate in this series was 6-methoxypurine 2',3'-dideoxynucleoside (1); however, the rate of dealkoxylation of 100 μM 1 was 0.17% of the rate of deamination of 100 μM 2',3'-dideoxyadenosine. Compound 17, the most potent anti-HIV-1 analog, was not a substrate for ADA. EHNA (erythro-9-(2-hydroxy- 3-nonyl)adenine), a potent inhibitor of ADA, had little effect on the antiviral activities of 17 and ddI. In contrast, coformycin, a potent inhibitor of both ADA and AMP deaminase, dramatically decreased the antiviral activity of 17, but not the antiviral activity of ddI. Thus, AMP deaminase appeared to be involved in the anabolism of 17. The pharmacokinetic profile of 17, the most promising analog in this series, was determined in the rat. At least seventeen metabolites of 17, including ddI, were detected in plasma samples. This analog also had poor oral bioavailability.
- Burns,St. Clair,Frick,Spector,Averett,English,Holmes,Krenitsky,Koszalka
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p. 378 - 384
(2007/10/02)
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- ANTISENSE NUCLEIC ACID DERIVATIVE
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A compound represented by general formula (1), its salt, and antiviral and antitumor drugs containing the same, wherein k is 0 to 20; m is 0 or 1; n is 4 to 29; X represents OH, methyl, sulfhydryl, C1 to C4 alkoxy or C1 to C6 monoalkylamino; Y and Z represent each O or S; R1, R2 and R3 may be the same or different from each other and each represents H, C1 to C6 alkyl, or C6 to C10 aryl which may have the substitutent(s) of group α; and D and B represent each independently a residue of any of the compounds of group β; provided that m is 0 when k is 0, and a base sequence containing B is complementary to a tumor gene or a virus gene: group α: OH, C1 to C6 alkyl, C1 to C6 alkoxy, methylenedioxy, nitro, azido, halogen, C6 to C10 aryl, C6 to C10 aryloxy, and aralkyloxy composed of a C6 to C10 aryl moiety and a C1 to C2 alkyl moiety, group β: adenine guanine, cytosine and thymine.
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- Intermolecular Radical C-C Bond Formation: Synthesis of a Novel Dinucleoside Linker for Non-anionic Antisense Oligonucleosides
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An efficient, stereoselective synthesis of a thymidine (T) nucleoside dimer (T-3'-CH2-NH-O-5'-T) 1 has been accomplished via an intermolecular radical reaction.The new dimer and methodology is useful for the development of backbone modified antisense oligonucleosides.Key Words: antisense oligonucleotides, nonionic backbone, intermolecular radical reaction
- Debart, Francoise,Vasseur, Jean-Jacques,Sanghvi, Yogesh S.,Cook, P. Dan
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p. 2645 - 2648
(2007/10/02)
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- Synthesis of 3'-fluoro-3'-deoxythymidine and studies of its 18F-radiolabeling, as a tracer for the noninvasive monitoring of the biodistribution of drugs against AIDS
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3'-Fluoro-3'-deoxy-thymidine (FDT), a fluorinated analog of 3'-azido-thymidine (AZT), is both more active against the HIV virus but also more toxic than AZT.Because of its fluorine atom, it can be labeled with 18F to be used to monitor this drug's biodistribution and targeting.A new synthesis for FDT, suited for 18F labeling, has been developed.After protecting the 5'-hydroxy group with a trityl group, the 3'-hydroxy group was substituted with a mesyl group in the lyxo configuration.Treatment with 18F potassium fluoride and crown-18 ether yielded the 18F-labeled fluoro derivative which on detritylation afforded 18F FDT with 7percent labeling efficiency.This is the first reported synthesis of 3'-fluoro-5'-O-trityl deoxythymidine using potassium fluoride and preparing its 18F labeled analog.The time required to incorporate 18F in the intermediate compound and isolate the end-product is reasonably short (approximately 2 h) which will allow sufficient time to conduct biological studies with this short-lived radionuclide.
- Wilson, I. K.,Chatterjee, S.,Wolf, W.
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p. 283 - 289
(2007/10/02)
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- Synthesis of 1-(3'-azido-2',3'-dideoxy-α-L-threo-pentofuranosyl)thymine as a potential anti-HIV agent
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Starting from methyl 2,3,5-tri-O-benzoyl-α-L-arabinofuranoside, a multistep synthesis of the C-4' epimer of AZT is described. Glycosylation of silylated thymine with 2,3,5-tri-O-benzoyl-L-arabinofuranosyl acetate (5) affords the α-nucleoside 7 after debenzoylation. Deoxygenation at C-2' of the selectively protected 8, followed by displacement of a 3'-methanesulfonyl group by lithium azide leads to the title compound which did not exhibit antiviral activity against HIV-1.
- Czernecki,Le Diguarher
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p. 683 - 686
(2007/10/02)
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- 5-substituted-2',3'-dideoxycytidine compounds with anti-HTLV-III activity
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5-substituted 2',3'-dideoxycytidine compounds and their monophosphates are disclosed which have been found to have potent activity against retroviruses. The 5-fluoro-and 5-aza-substituted 2',3'-dideoycytidine compounds have been found to be effective against HTLV-III/LAV virus.
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- Antiviral activity, antimetabolic activity and cytotoxicity of 3'-substituted deoxypyrimidine nucleosides
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The antiviral activity, effect on cellular DNA and RNA synthesis, and cytotoxicity toward mammalian cells of 5-fluoro-2'-deoxyuridine, 5-methoxymethyl-2'-deoxyuridine, 2'-deoxythymidine, and their corresponding 3'-p-nitrophenylphosphate and 3'-p-aminophenylphosphate derivatives were determined. The 3'-p-aminophenylphosphate-2'-deoxy-5-methoxymethyluridine derivative was as potent as 5-methoxymethyl-2'-deoxyuridine in inhibiting herpes simplex viruses; however, 3'-p-aminophenylphosphate-2'-deoxy-5-fluorouridine was less potent than 5-fluoro-2'-deoxyuridine in inhibiting viral replication. The results suggest that the deoxypyrimidine ribonucleoside kinase has bulk tolerance for substituents at the 3-position of the ribofuranose moiety. The effect on cellular DNA and RNA synthesis and cytotoxicity toward mammalian cells were monitored by studying the incorporation of radioactive precursors. 5-Methoxymethyl-2'-deoxyuridine and 3'-p-aminophenylphosphate-2'-deoxy-5-methoxymethyluridine failed to inhibit DNA or RNA synthesis. 5-Fluoro-2'-deoxyuridine and 3'-p-aminophenylphosphate-2'-deoxy-5-fluorouridine decreased incorporation of [3H]deoxyuridine by 50% at 1.0 and 40 μM, respectively. Cytotoxicity (microscopic lesions using monolayer cells) on exposure to 5-methoxymethyl-2'-deoxyuridine, 3'-p-aminophenylphosphate-2'-deoxy-5-methoxymethyluridine, 5-fluoro-2'-deoxyuridine, and 3'-p-aminophenylphosphate-2'-deoxy-5-fluorouridine was observed at 3800, 1600, 1.6, and 110 μM, respectively.
- Stuart,Ayisi,Tourigny,Gupta
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p. 246 - 249
(2007/10/02)
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- 2' AND 3'-KETONUCLEOSIDES AND THEIR ARABINO AND XYLO REDUCTION PRODUCTS CONVENIENT ACCESS VIA SELECTIVE PROTECTION AND OXIDATION OF RIBONUCLEOSIDES
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A number of 2',5'- or 3',5'-diprotected ribonucleosides and 5'-protected 2'- or 3'-deoxy-β-D-erythro-pentofuranosyl nucleosides have been oxidized to the corresponding 3' or 2'-ketonucleoside derivatives using chromium trioxide/pyridine/acetic anhydride or dimethyl sulfoxide/acetic anhydride.Reduction of the carbonyl functions with sodium borohydride gave the inverted arabino, xylo, or deoxy-threo isomers as predominant products by attack at the less hindered α-face of the sugar ring.Parallel reductions using sodium borodeuteride corroborated the epimeric ratios by demonstrating that complete oxidation of the original hydroxyl groups had occured.The deuterium labeling also aided in making NMR spectral assignments.
- Hansske, Fritz,Madej, Danuta,Robins, Morris J.
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p. 125 - 135
(2007/10/02)
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- THE 2-(METHYLTHIOMETHOXY)ETHOXYCARBONYL PROTECTING GROUP
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Alcohols (ROH) may be converted into their MTMEC derivatives (6) by acylation with 2-(methylthiomethoxy)ethoxycarbonyl chloride (5); the MTMEC "protected protecting group" may be removed by treatment first with Hg(II) perchlorate in the presence of 2,4,6-collidine or pyridine in aceton-water solution, followed by hydrolysis under very mild basic conditions.
- Jones, Simon S.,Reese, Colin B.,Sibanda, Samson
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p. 1933 - 1936
(2007/10/02)
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