Antisense oligodeoxynucleotides: synthesis, biophysical and biological evaluation of oligodeoxynucleotides containing modified pyrimidines

Sanghvi, Yogesh S.; Hoke, Glenn D.; Freier, Susan M.; Zounes, Maryann; Gonzalez, C.; Cummins, Lendell L.; Sasmor, Henri; Cook, P. Dan

doi:10.1093/nar/21.14.3197

Cited by 71 publications

(44 citation statements)

References 27 publications

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“…The complex can inhibit production of protein from the gene by direct blockage of m-RNA or through RNase H catalyzed degradation of RNA in the double-stranded region (cf. Zon, 1988;Thuong and Helene, 1993;Sanghvi et al, 1993). The added strand is typically DNA due to the greater stability and ease of synthesis of DNA relative to RNA.…”

Section: Introductionmentioning

confidence: 99%

The interaction of intercalators and groove‐binding agents with DNA triple‐helical structures: The influence of ligand structure, DNA backbone modifications and sequence

Wilson

Mizan

Tanious

et al. 1994

J of Molecular Recognition

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The effects of ligand structure and properties, DNA backbone modifications and DNA sequence on the interaction of a variety of well-known groove-binding agents and intercalators with DNA duplexes and triplexes have been evaluated by thermal melting experiments and molecular modeling. Both methylphosphonate and phosphorothioate substitutions generally destabilize DNA duplexes and triplexes. Modified duplexes can be strongly stabilized by both groove-binding agents and intercalators whereas triplexes are primarily stabilized by intercalators. Of the compounds tested, the intercalators coralyne and quinacrine provide the largest stabilization of the triplex dT19.dA19.dT19. Molecular modeling studies suggest that the large intercalating ring system of coralyne stacks well with the triplex bases whereas the alkylamino side chain of quinacrine fits snugly into the remaining space of the major groove of dT19.dA19.dT19 triplex and forms extensive van der Waals contacts with the thymine methyl groups that line the groove. Converting some of the T.A.T base triples to C+.G.C (e.g. dT19.dA19.dT19 to d(T4C+)3T4.d(A4G)3A4.(T4C)3T4) causes very significant decreases in observed Tm increases for compounds such as quinacrine and coralyne. Although removal of thymine methyl groups and addition of positive charge on substitution of C+.G.C for T.A.T should reduce binding of cationic intercalators, the large difference observed between the pure AT and the mixed sequence triplexes suggest that they may also have differences in structure and properties.

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Section: Introductionmentioning

confidence: 99%

The interaction of intercalators and groove‐binding agents with DNA triple‐helical structures: The influence of ligand structure, DNA backbone modifications and sequence

Wilson

Mizan

Tanious

et al. 1994

J of Molecular Recognition

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“…The stabilization results from hydrophobic effects generated by a release of hydrating water molecules from the double helix to the bulk. Duplex stability is also enhanced by m C due to an increase in hydrophobic interactions with the neighboring bases 5,7,8) (Fig. 1).…”

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confidence: 99%

“…Analogous to m C, 5-bromocytosine ( Br C) stabilizes duplex formation when Br C-modified oligonucleotides are used. 5,8) Introduction of substituents at the C-5 position of uracil, such as a methyl group or halogen atoms, increases the stability of triplexes and duplexes formed 5,[9][10][11] (Fig. 1).…”

mentioning

confidence: 99%

Triplex- and Duplex-Forming Abilities of Oligonucleotides Containing 2′-Deoxy-5-trifluoromethyluridine and 2′-Deoxy-5-trifluoromethylcytidine

Ito

Matsuo

Osawa

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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A facile synthesis of 2′-deoxy-5-trifluoromethyluridine and 2′-deoxy-5-trifluoromethylcytidine phosphoramidites from commercially available 2′-deoxyuridine and 2′-deoxycytidine was achieved, respectively. The obtained phosphoramidites were incorporated into oligonucleotides, and their binding affinity to doublestranded DNA (dsDNA) and single-stranded RNA (ssRNA) was evaluated by UV-melting experiments. The triplex-forming abilities of oligonucleotides including 5-trifluoromethylpyrimidine nucleobases with dsDNA were decreased. Especially, the stability of the triplex containing a trifluoromethylcytosine ( CF3 C)-GC base triplet was low, likely due to the low pK a of protonated CF3 C by the electron-withdrawing trifluoromethyl group. A slight decrease in stability of the duplex formed with ssRNA by oligonucleotides including 5-trifluoromethylpyrimidine nucleobases was only observed, suggesting that they might be applicable to various ssRNA-targeted technologies using features of fluorine atoms.

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“…In fact, substitution of a thymine base with a uracil base generally results in a decrease in T m of ca. 0.58 per substitution [54], which further emphasizes the detrimental effect of the 4'-C-(aminomethyl) group on the T m value obtained for XIII. As expected, 2'-O-methyl-modified oligonucleotide XII showed increased binding affinity towards RNA (DT m /2'-Omethylnucleotide 1.68) compared to the 2'-deoxy analog V. ON XIII showed significantly reduced binding affinity towards RNA in both salt buffers compared to the reference strand XII, but still increased binding affinity towards RNA compared to the completely unmodified 2'-deoxy analog V. Likewise, the 2'-deoxy-2'-fluoro monomer Y was incorporated in an otherwise 2'-O-methyl modified ON (XIV, Table 1).…”

mentioning

confidence: 63%

Oligonucleotides Containing Novel 4′-C- or 3′-C-(Aminoalkyl)-Branched Thymidines

Pfundheller¹,

Bryld²,

Olsen³

et al. 2000

HCA

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The synthesis of four novel 3′‐C‐branched and 4′‐C‐branched nucleosides and their transformation into the corresponding 3′‐O‐phosphoramidite building blocks for automated oligonucleotide synthesis is reported. The 4′‐C‐branched key intermediate 11 was synthesized by a convergent strategy and converted to its 2′‐O‐methyl and 2′‐deoxy‐2′‐fluoro derivatives, leading to the preparation of novel oligonucleotide analogues containing 4′‐C‐(aminomethyl)‐2′‐O‐methyl monomer X and 4′‐C‐(aminomethyl)‐2′‐deoxy‐2′‐fluoro monomer Y (Schemes 2 and 3). In general, increased binding affinity towards complementary single‐stranded DNA and RNA was obtained with these analogues compared to the unmodified references (Table 1). The presence of monomer X or monomer Y in a 2′‐O‐methyl‐RNA oligonucleotide had a negative effect on the binding affinity of the 2′‐O‐methyl‐RNA oligonucleotide towards DNA and RNA. Starting from the 3′‐C‐allyl derivative 28, 3′‐C‐(3‐aminopropyl)‐protected nucleosides and 3′‐O‐phosphoramidite derivatives were synthesized, leading to novel oligonucleotide analogues containing 3′‐C‐(3‐aminopropyl)thymidine monomer Z or the corresponding 3′‐C‐(3‐aminopropyl)‐2′‐O,5‐dimethyluridine monomer W (Schemes 4 and 5). Incorporation of the 2′‐deoxy monomer Z induced no significant changes in the binding affinity towards DNA but decreased binding affinity towards RNA, while the 2′‐O‐methyl monomer Z induced decreased binding affinity towards DNA as well as RNA complements (Table 2).

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Antisense oligodeoxynucleotides: synthesis, biophysical and biological evaluation of oligodeoxynucleotides containing modified pyrimidines

Cited by 71 publications

References 27 publications

The interaction of intercalators and groove‐binding agents with DNA triple‐helical structures: The influence of ligand structure, DNA backbone modifications and sequence

The interaction of intercalators and groove‐binding agents with DNA triple‐helical structures: The influence of ligand structure, DNA backbone modifications and sequence

Triplex- and Duplex-Forming Abilities of Oligonucleotides Containing 2′-Deoxy-5-trifluoromethyluridine and 2′-Deoxy-5-trifluoromethylcytidine

Oligonucleotides Containing Novel 4′-C- or 3′-C-(Aminoalkyl)-Branched Thymidines

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