Biophysical and biochemical properties of oligodeoxynucleotides containing 4′-C- and 5′-C-substituted thymidines

Wang, Guangyi; Middleton, Patrick J.; Lin, Catherine J.; Pietrzkowski, Zbigniew

doi:10.1016/s0960-894x(99)00103-1

Cited by 13 publications

(8 citation statements)

References 20 publications

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“…Concerning the thermal stability of the resulting duplexes, a penalty is paid in all cases, probably due to a combination of slight sterical disturbance and a distortion of the duplex hydration. Small 5'-C-substituents, like methyl, hydroxymethyl and others, have earlier demonstrated relatively small but unavoidable decreases in duplex stabilities (DT m values of 1-3 8C for each incorporation), [21][22][23] and these thermal penalties seem to increase with the sterical bulk of the substituent. Leumann and co-workers inserted hydrophobic butyl and isopentyl substituents and observed decreases of around 2-3 8C.…”

Section: Discussionmentioning

confidence: 91%

Synthesis and Molecular Modelling of Double‐Functionalised Nucleosides with Aromatic Moieties in the 5′‐(S)‐Position and Minor Groove Interactions in DNA Zipper Structures

Shaikh

Madsen

Nielsen

et al. 2010

Chemistry A European J

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A series of six double-functionalised nucleosides, in which aromatic moieties were inserted into the 5'-(S)-C-position, were synthesised and incorporated into DNA duplexes. The aromatic moieties were thymine-1-yl, phenyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 4-(uracil-5-yl)-1,2,3-triazol-1-yl and 4-phenyl-1,2,3-triazol-1-yl. The DNA duplexes were studied with UV melting curves, CD spectroscopy and molecular modelling. The results showed that the aromatic moieties in some cases interact in the minor groove forming DNA zipper structures. The strongest specific interaction was found between two thymines or between a thymine and a phenyl group in a crossed (-3)-zipper motif (i.e., with two base pairs interspacing the modifications). Modelling revealed that the interaction is aromatic stacking across the minor groove. Also, the extended uracil-triazole moiety demonstrated zipper contacts in the minor groove as well as binding to the floor of the groove.

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Section: Discussionmentioning

confidence: 91%

Synthesis and Molecular Modelling of Double‐Functionalised Nucleosides with Aromatic Moieties in the 5′‐(S)‐Position and Minor Groove Interactions in DNA Zipper Structures

Shaikh

Madsen

Nielsen

et al. 2010

Chemistry A European J

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“…The attachment of an aminoalkyl-group to the 4’-position ( Table 7A ) offers an advantage since this site is in close proximity to the backbone, which potentially allows the basic amino group via a relative short linking group to engage electrostatically with the acidic phosphodiester moiety [ 97 ]. This was initially explored for ONs containing 4′- C -(aminomethyl)thymidine (monomer 63 ) [ 98 – 99 ]. Later, the amine-functionalized group was expanded into the monomer 4′- C -(2-(( N- (2-aminoethyl)carbamoyl)oxy)ethyl)thymidine (not shown) that was shown to display improved resistance against endo- and exonuclease cleavage relative to the DNA control ON [ 100 ].…”

Section: Reviewmentioning

confidence: 99%

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

Danielsen¹,

Wengel²

2021

Beilstein J. Org. Chem.

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Antisense oligonucleotides (ASOs) have the ability of binding to endogenous nucleic acid targets, thereby inhibiting the gene expression. Although ASOs have great potential in the treatment of many diseases, the search for favorable toxicity profiles and distribution has been challenging and consequently impeded the widespread use of ASOs as conventional medicine. One strategy that has been employed to optimize the delivery profile of ASOs, is the functionalization of ASOs with cationic amine groups, either by direct conjugation onto the sugar, nucleobase or internucleotide linkage. The introduction of these positively charged groups has improved properties like nuclease resistance, increased binding to the nucleic acid target and improved cell uptake for oligonucleotides (ONs) and ASOs. The modifications highlighted in this review are some of the most prevalent cationic amine groups which have been attached as single modifications onto ONs/ASOs. The review has been separated into three sections, nucleobase, sugar and backbone modifications, highlighting what impact the cationic amine groups have on the ONs/ASOs physiochemical and biological properties. Finally, a concluding section has been added, summarizing the important knowledge from the three chapters, and examining the future design for ASOs.

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“…Interestingly, A quick inspection of the B-DNA helical structure indicates that a substituent at the 5 -C with the "S" configuration will point into the minor groove and therefore would compete with the solvating water molecules and also could interact with opposite phosphate groups depending on the length of the grafted chain. It has been shown that such modifications including alkyl [31], allyl, hydroxypropyl or aminomethyl [32], within oligonucleotides induced significant loss in thermal stability of duplexes built with DNA counterparts. Only aminopropyl-aminopentenyl substituent [11] exhibited a slight improvement in the thermal stability that could be attributed to a favorable interaction of the protonated amino group with the opposite phosphate group.…”

Section: Three Way Junctions Assemblies and Thermal Denaturation Studiesmentioning

confidence: 99%

DNA Three Way Junction Core Decorated with Amino Acids-Like Residues-Synthesis and Characterization

et al. 2016

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Construction and physico-chemical behavior of DNA three way junction (3WJ) functionalized by protein-like residues (imidazole, alcohol and carboxylic acid) at unpaired positions at the core is described. One 5 -C(S)-propargyl-thymidine nucleotide was specifically incorporated on each strand to react through a post synthetic CuACC reaction with either protected imidazolyl-, hydroxyl-or carboxyl-azide. Structural impacts of 5 -C(S)-functionalization were investigated to evaluate how 3WJ flexibility/stability is affected.

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Biophysical and biochemical properties of oligodeoxynucleotides containing 4′-C- and 5′-C-substituted thymidines

Cited by 13 publications

References 20 publications

Synthesis and Molecular Modelling of Double‐Functionalised Nucleosides with Aromatic Moieties in the 5′‐(S)‐Position and Minor Groove Interactions in DNA Zipper Structures

Synthesis and Molecular Modelling of Double‐Functionalised Nucleosides with Aromatic Moieties in the 5′‐(S)‐Position and Minor Groove Interactions in DNA Zipper Structures

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

DNA Three Way Junction Core Decorated with Amino Acids-Like Residues-Synthesis and Characterization

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