- Structure and dynamics of disulfide cross-linked DNA triple helices
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The design, synthesis, and characterization of two disulfide cross-linked intramolecular pyr·pur-pyr triple helices (IV and V) is presented. Placement of a covalent cross-link from the Hoogsteen strand to the Watson-Crick duplex produces two fundamental changes in the cross-linked DNAs relative to the parent sequence. First, formation of the cross-link results in an increase in the apparent pK(a) of the Hoogsteen cytosines by 1.5 pK(a) units (to 8.6 and 8.3 for IV and V, respectively) with a concomitant increase in thermal stability of ~40°C at pH 7.4. Second, the cross-link enforces the triplex structure over a wide range of solution conditions, including those that are physiologically relevant (e.g., pH 7.4, 155 mM Na+, 37°C). CD and NMR measurements indicate that the cross-link does not significantly perturb the geometry of IV and V relative to their unmodified counterpart. Because the disulfide crosslink effectively prevents conformational heterogeneity associated with pyr·pur-pyr triple helices containing C+·G-C base-triplets at neutral pH, constructs possessing this modification can serve as model systems to examine the structural and thermodynamic aspects of triplex formation in vitro and to aid in the development of sequences that bind with higher affinity and specificity.
- Osborne, Scott E.,Cain, Robert J.,Glick, Gary D.
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p. 1171 - 1182
(2007/10/03)
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- Incorporation of Alkylthiol Chains at C-5 of Deoxyuridine
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A series of alkylthiol-tether homologs at C-5 of 2'deoxyuridine have been synthetized and incorporated into DNA oligomers through solid-phase DNA phosphoramidite synthesis.DNA-ligand disulfide crosslinks have been initially addressed through formation of an n-butyl-DNA disulfide conjugate.
- Goodwin, Jay T.,Glick, Gary D.
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p. 5549 - 5552
(2007/10/02)
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- PALLADIUM-CATALYZED CROSS-COUPLING REACTION OF ORGANOSTANNANES WITH NUCLEOSIDE HALIDES
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A general reaction is described for the synthesis of C-5 substituted nucleosides through the coupling of organostannanes with nucleoside-palladium intermediate derived in situ from 5-iodouridine (or 5-iodo-2'-deoxyuridine) and .The reaction was used for the synthesis of C-5 aryl, heteroaryl, vinyl, allyl and alkyl substituted nucleosides.
- Hassan, Mohamed Ezeldin
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p. 1944 - 1948
(2007/10/02)
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- Photochemistry of 5- and 6-Iodouracils in the Presence of Allylsilanes and Alkenes. A Convenient Route to C5- and C6-Substituted Uracils
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The photocoupling reaction of 5- and 6-iodouracil derivatives with allylsilanes and alkenes is presented.Irradiation of 5-iodouridine (5) and 5-iodo-2'-deoxyuridine (6) in the presence of allyltrimethylsilane in aqueous acetonitrile gave 5-allyluridine (7) and 5-allyl-2'-deoxyuridine, respectively.Irradiation of 6-iodo-1,3-dimethyluracil (11) in the presence of allylsilanes and alkyl-substituted olefins produced the corresponding C6-substituted uracil derivatives in good yields. 5-Fluoro-6-iodo-1,3-dimethyluracil (12) underwent a similar photocoupling reaction with allylsilanes and alkenes.The photocoupling reaction provides a convenient method for carbon-carbon bond formation at the C5 or C6 position of uracil derivatives.A radical addition mechanism has been proposed for this novel photocoupling reaction.
- Saito, Isao,Ikehira, Hideyuki,Matsuura, Teruo
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p. 5148 - 5153
(2007/10/02)
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- A FACILE PHOTOCHEMICAL ROUTE TO C-5 AND C-6 ALLYL-SUBSTITUTED URACIL NUCLEOSIDES
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Irradiation of 5-iodouridine or 6-iodo-1,3-dimethyluracil in aq. acetonitrile in the presence of allyltrimethylsilane provided the corresponding 5- or 6-allylated product.
- Saito, Isao,Ikehira, Hideyuki,Matsuura, Teruo
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p. 1993 - 1994
(2007/10/02)
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- Structural requirements of olefinic 5-substituted deoxyuridines for antiherpes activity
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A number of structurally related 5-substituted pyrimidine 2'-deoxyrubinucleosides were synthesized and tested for antiviral activity against herpes simplex virus type 1 (HSV-1) in cell culture. A minimum inhibitory concentration was determined for each compound, and from a comparison of these values a number of conclusions were drawn with regard to those molecular features that enhance or reduce antiviral activity. Optimum inhibition of HSV-1 in cell culture occurred when the 5-substituent was unsaturated and conjugated with the pyrimidine ring, was not longer than four carbon atoms in length, had E stereochemistry, and included a hydrophobic, electronegative function but did not contain a branching point. Such features are contained in (E)-5-(2-bromovinyl)-2'-deoxyuridine, which was the most active of the compounds described.
- Goodchild,Porter,Raper,Sim,Upton,Viney,Wadsworth
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p. 1252 - 1257
(2007/10/02)
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- C-5-Substituted Pyrimidine Nucleosides. 3. Reaction of Allylic Chlorides, Alcohols, and Acetates with Pyrimidine Nucleoside Derived Organopalladium Intermediates
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The reaction of allylic chlorides with pyrimidine nucleoside derived organopalladium intermediates was investigated.The organopalladium intermediates were generated in situ by the reaction of 5-(chloromercuri)-2'-deoxyuridine (1), 5-(chloromercuri)cytidine, and 5-(chloromercuri)-2'-deoxycytidine with a catalytic amount of Li2PdCl4 in methanol.With allyl chloride, 1 gives principally 5-allyl-2'-deoxyuridine, some of which reacts further with 1 to give the cross-linked nucleosides (E)-5--2'-deoxyuridine (5) and5--2'-deoxyuridine (6). 3-Chloro-1-butene couples with 1 to give mainly (E)-5-(2-buten-1-yl)-2'-deoxyuridine (9) and lesser amounts of the Z isomer 10 and 5-(1-methyl-2-propen-1-yl)-2'-deoxyuridine (11).Nucleoside 11 appears to be the product of a coupling reaction between 1-methoxy-2-butene and the organopalladium intermediate derived from 1.Allylic chlorides are transformed to allyl methyl ethers in 0.1 M Li2PdCl4 at a slightly slower rate than the coupling reaction.Higher allylic chloride homologues show greater regioselectivity and stereoselectivity. 3-Chloro-1-pentene leads to (E)-5-(2-penten-1-yl)-2'-deoxyuridine (14) as the sole major product in 50percent yield.When a cyano group was attached to C-5 of 3-chloro-1-pentene, the resultant allylic chloride coupled regioselectivity but gave both cis and trans isomers.The mechanism of the coupling reaction is discussed and a basis for stereoselectivity proposed.Allylic alcohols and acetates couple more slowly and less cleanly, leading to lower yields of the same allylic-substituted pyrimidine nucleosides obtained with allylic chlorides.In some instances other products could be isolated.Nucleoside 1 and 3-hydroxy-4-methyl-1-pentene gave 5-(4-methyl-2-penten-1-yl)-2'-deoxyuridine (16) as well as 5-(4-methyl-3-oxopentyl)-2'-deoxyuridine (20). 3-Acetoxy-4-methyl-1-pentene led to (E)-5-(4-methyl-1,3-pentadien-1-yl)-2'-deoxyuridine (23).Mechanisms leading to these products are discussed.
- Bergstrom, Donald E.,Ruth, Jerry L.,Warwick, Paul
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p. 1432 - 1441
(2007/10/02)
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