Synthesis of triazole-linked morpholino oligonucleotides via Cu<sup>I</sup> catalysed cycloaddition

Palframan, M. J.; Alharthy, Rima D.; Powalowska, Paulina; Hayes, Christopher J.

doi:10.1039/c6ob00007j

Cited by 22 publications

(18 citation statements)

References 27 publications

(23 reference statements)

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“…UV melting was used to determine the melting temperature (Tm) of ON 1-4 against DNA (Figure 4) and RNA (Figure 5), and the Tms are listed in Table 1. We have previously used ON 1 in NMR studies to explain the biocompatibility of the DNA triazole linkage and the Tms of the DNA:DNA 24 and DNA:RNA 37 duplexes have been reported, providing a benchmark for this work.…”

Section: Dna and Rna Duplex Stabilitymentioning

confidence: 99%

Searching for the ideal triazole: Investigating the 1,5-triazole as a charge neutral DNA backbone mimic

et al. 2020

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A novel triazole linkage that mimics the phosphodiester backbone in DNA was designed, synthesised and evaluated. Unlike previous work which utilised copper to form a 1,4 triazole linkage in the DNA backbone, a ruthenium catalyst was used to yield a 1,5 triazole. The artificial linkage was incorporated into a DNA backbone via a phosphoramidite building block using solid phase synthesis. The biophysical properties of DNA with a 1,5 triazole linkage in the backbone were evaluated by UV melting and circular dichroism and compared to DNA modified with previously reported 1,4 triazole linkages of various lengths.

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Section: Dna and Rna Duplex Stabilitymentioning

confidence: 99%

Searching for the ideal triazole: Investigating the 1,5-triazole as a charge neutral DNA backbone mimic

et al. 2020

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“…1c ) have been shown to hybridize to their RNA targets with slightly improved affinity compared to triazole alone. 15 However, the resulting duplexes remain thermally less stable than their unmodified counterparts.…”

mentioning

confidence: 99%

Locked nucleic acid (LNA) enhances binding affinity of triazole-linked DNA towards RNA

et al. 2017

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“…In the case of GMO-PMO/PMO-GMO chimeras, no such delivery vehicle is required and showed the antisense efficacy as low as 750 nM dose in in vitro and required as minimum as four guanidinium linkages. Though, backbone modified PMO and their chimeras [59,60] or PMO-DNA chimera [61] or chimeric oligonucleotides containing morpholino thymidine analogues [62,63] or with a single guanidinium morpholino unit incorporated DNA [64] has been reported earlier however, to the best of our knowledge, GMO-PMO/PMO-GMO chimera is the first report from our group. Considering the simplicity, the possibility of rational design, relatively inexpensive and easy synthesis, GMO-PMO/PMO-GMO self-transfecting chimera, in principle could be useful as tools to target any gene including virus and bacteria towards the development of antisense therapy and could be a practical approach.…”

Section: Discussionmentioning

confidence: 94%

Self-transfecting GMO-PMO and PMO-GMO chimeras enable gene silencingin vitro and in vivozebrafish model and NANOG Inhibition Induce the Apoptosis in Breast and Prostate Cancer Cells

Kundu

Das

Bose

et al. 2021

Preprint

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Phosphorodiamidate Morpholino Oligonucleotides (PMOs)-based antisense reagents cannot enter inside cells by itself without the help of any delivery technique which is the last hurdle for their clinical applications. To overcome this limitation, a self-transfecting GMO-PMO or PMO-GMO chimeras has been explored as a gene silencing reagent where GMO stands for guanidinium morpholino oligonucleotides which linked either at the OH- or NH-end of PMOs. GMO not only facilitates cellular internalization of such chimeras but also participates in Watson-Crick base pairing during gene silencing in ShhL2 cells when designed against mGli1 and compared with scrambled GMO-PMO where mutations were made only to the GMO part. GMO-PMO-mediated knockdown of no tail gene resulted no tail-dependent phenotypes in zebrafish and worked even after the delivery at 16-, 32- and 64-cell stages which were previously unachievable by regular PMO. Furthermore, GMO-PMO chimeras has shown the inhibition of NANOG, a key regulator of self-renewal and pluripotency of both embryonic and cancer stem cells. Its inhibition influences on the expression of other cancer related proteins and the respective phenotypes in breast cancer cells and increases the therapeutic potential of taxol. To the best of our knowledge, this is the first report on the self-transfecting antisense reagents since the discovery of guanidinium linked DNA (DNG) and most effective among the all cell-penetrating PMOs reported till date expected to solve the longstanding problem of PMO delivery. In principle, this technology could be useful for the inhibition of any target gene without using any delivery vehicle and should have applications in the fields of antisense therapy, diagnostic and nanotechnology area.

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Synthesis of triazole-linked morpholino oligonucleotides via Cu^I catalysed cycloaddition

Abstract: Triazole-linked morpholino (TLMO) oligonucleic acids were synthesised using the CuI catalysed (3 + 2) azide–alkyne cycloaddition (CuAAC) reaction.

Cited by 22 publications

References 27 publications

Searching for the ideal triazole: Investigating the 1,5-triazole as a charge neutral DNA backbone mimic

Searching for the ideal triazole: Investigating the 1,5-triazole as a charge neutral DNA backbone mimic

Locked nucleic acid (LNA) enhances binding affinity of triazole-linked DNA towards RNA

Self-transfecting GMO-PMO and PMO-GMO chimeras enable gene silencingin vitro and in vivozebrafish model and NANOG Inhibition Induce the Apoptosis in Breast and Prostate Cancer Cells

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Synthesis of triazole-linked morpholino oligonucleotides via CuI catalysed cycloaddition

Abstract: Triazole-linked morpholino (TLMO) oligonucleic acids were synthesised using the CuI catalysed (3 + 2) azide–alkyne cycloaddition (CuAAC) reaction.

Cited by 22 publications

References 27 publications

Searching for the ideal triazole: Investigating the 1,5-triazole as a charge neutral DNA backbone mimic

Searching for the ideal triazole: Investigating the 1,5-triazole as a charge neutral DNA backbone mimic

Locked nucleic acid (LNA) enhances binding affinity of triazole-linked DNA towards RNA

Self-transfecting GMO-PMO and PMO-GMO chimeras enable gene silencingin vitro and in vivozebrafish model and NANOG Inhibition Induce the Apoptosis in Breast and Prostate Cancer Cells

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Synthesis of triazole-linked morpholino oligonucleotides via Cu^I catalysed cycloaddition