Synthesis and Triplex Formation of Oligonucleotides Containing 8-Thioxodeoxyadenosine

Miyata, Kenichi; Tamamushi, Ryuji; Tsunoda, Hirosuke; Ohkubo, Akihiro; Seio, Kohji; Sekine, Mitsuo

doi:10.1021/ol802622s

Cited by 17 publications

(21 citation statements)

References 27 publications

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“…The stabilization effect of L modification may also result from the improved van der Waals contact between a sulfur atom in an L nucleobase in a triplex-forming PNA (TFPNA) and an H 8 atom of a guanine in an RNA duplex (Figure 1C and H) (38,57,58). Furthermore, a nucleobase L (with a relatively more polarizable and less electronegative thio group) has enhanced stacking interactions with flanking nucleobases and has a reduced dehydration penalty (14,38,44,54,57–60).…”

Section: Resultsmentioning

confidence: 99%

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Incorporation of thio-pseudoisocytosine into triplex-forming peptide nucleic acids for enhanced recognition of RNA duplexes

Devi

Yuan

et al. 2014

Nucleic Acids Research

173

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Peptide nucleic acids (PNAs) have been developed for applications in biotechnology and therapeutics. There is great potential in the development of chemically modified PNAs or other triplex-forming ligands that selectively bind to RNA duplexes, but not single-stranded regions, at near-physiological conditions. Here, we report on a convenient synthesis route to a modified PNA monomer, thio-pseudoisocytosine (L), and binding studies of PNAs incorporating the monomer L. Thermal melting and gel electrophoresis studies reveal that L-incorporated 8-mer PNAs have superior affinity and specificity in recognizing the duplex region of a model RNA hairpin to form a pyrimidine motif major-groove RNA2–PNA triplex, without appreciable binding to single-stranded regions to form an RNA–PNA duplex or, via strand invasion, forming an RNA–PNA2 triplex at near-physiological buffer condition. In addition, an L-incorporated 8-mer PNA shows essentially no binding to single-stranded or double-stranded DNA. Furthermore, an L-modified 6-mer PNA, but not pseudoisocytosine (J) modified or unmodified PNA, binds to the HIV-1 programmed −1 ribosomal frameshift stimulatory RNA hairpin at near-physiological buffer conditions. The stabilization of an RNA2–PNA triplex by L modification is facilitated by enhanced van der Waals contacts, base stacking, hydrogen bonding and reduced dehydration energy. The destabilization of RNA–PNA and DNA–PNA duplexes by L modification is due to the steric clash and loss of two hydrogen bonds in a Watson–Crick-like G–L pair. An RNA2–PNA triplex is significantly more stable than a DNA2–PNA triplex, probably because the RNA duplex major groove provides geometry compatibility and favorable backbone–backbone interactions with PNA. Thus, L-modified triplex-forming PNAs may be utilized for sequence-specifically targeting duplex regions in RNAs for biological and therapeutic applications.

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Section: Resultsmentioning

confidence: 99%

“…The advantage of a neutral nucleobase L is that the triplex formation has low pH and salt dependence, as discussed above. In addition, the potential destabilizing effect due to charge–charge repulsion between adjacent positively charged C + ∙G–C base triples (25,58) is not expected for neutral L∙G–C base triples.…”

Section: Resultsmentioning

confidence: 99%

Incorporation of thio-pseudoisocytosine into triplex-forming peptide nucleic acids for enhanced recognition of RNA duplexes

Devi

Yuan

et al. 2014

Nucleic Acids Research

173

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“…For example, TFOs containing LNAs/BNAs ( 13 ) and 5-propynylpyrimidines ( 17 ) more strongly bind to targeted DNA duplexes than unmodified TFOs. A recent study conducted by us yielded the interesting result that the strong stacking effect of thiocarbonyl groups of 2’-OMe-2-thiothymidine ( 2’-OMe s T; Figure 1a ) ( 19 ) and 2’-OMe-8-thioadenosine ( 2’-OMe s A; Figure 1b ) ( 19 , 20 ) can increase the binding affinities of TFOs.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and triplex-forming properties of oligonucleotides capable of recognizing corresponding DNA duplexes containing four base pairs

Ohkubo

Yamada

et al. 2015

Nucleic Acids Res

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A triplex-forming oligonucleotide (TFO) could be a useful molecular tool for gene therapy and specific gene modification. However, unmodified TFOs have two serious drawbacks: low binding affinities and high sequence-dependencies. In this paper, we propose a new strategy that uses a new set of modified nucleobases for four-base recognition of TFOs, and thereby overcome these two drawbacks. TFOs containing a 2’-deoxy-4N-(2-guanidoethyl)-5-methylcytidine (dgC) residue for a C-G base pair have higher binding and base recognition abilities than those containing 2’-OMe-4N-(2-guanidoethyl)-5-methylcytidine (2’-OMegC), 2’-OMe-4N-(2-guanidoethyl)-5-methyl-2-thiocytidine (2’-OMegCs), dgC and 4S-(2-guanidoethyl)-4-thiothymidine (gsT). Further, we observed that N-acetyl-2,7-diamino-1,8-naphtyridine (DANac) has a higher binding and base recognition abilities for a T-A base pair compared with that of dG and the other DNA derivatives. On the basis of this knowledge, we successfully synthesized a fully modified TFO containing DANac, dgC, 2’-OMe-2-thiothymidine (2’-OMesT) and 2’-OMe-8-thioxoadenosine (2’-OMesA) with high binding and base recognition abilities. To the best of our knowledge, this is the first report in which a fully modified TFO accurately recognizes a complementary DNA duplex having a mixed sequence under neutral conditions.

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“…The elongation and deprotection of TFOs containing consecutive thionucleoside residues was performed using these phosphoramidite units in a DNA synthesizer by the general procedure. Interestingly, during deprotection of the 2-(trimethylsilyl)ethylthio (TMSES) group from the protected s 8 A and s 8 I species in 2 0 -OMe RNAs, we found that the desulfurization of the thiocarbonyl group occurred when TFOs 11 and 12 were treated with tetrabutylammonium fluoride (TBAF) for more than 1 h, although such a thiocarbonyl group in DNA was stable under the same conditions for 2 h. 8 Therefore, the TMSES group was deprotected by treatment with 1 M TBAF in THF for a short time of 30 min in the synthesis of TFOs 11 and 12. After TFOs were released from resins, they were isolated by HPLC and characterized by MALDI-TOF mass spectrometry.…”

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confidence: 96%

Stable triplex formation using the strong stacking effect of consecutive thionucleoside moieties

et al. 2011

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Synthesis and Triplex Formation of Oligonucleotides Containing 8-Thioxodeoxyadenosine

Cited by 17 publications

References 27 publications

Incorporation of thio-pseudoisocytosine into triplex-forming peptide nucleic acids for enhanced recognition of RNA duplexes

Incorporation of thio-pseudoisocytosine into triplex-forming peptide nucleic acids for enhanced recognition of RNA duplexes

Synthesis and triplex-forming properties of oligonucleotides capable of recognizing corresponding DNA duplexes containing four base pairs

Stable triplex formation using the strong stacking effect of consecutive thionucleoside moieties

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