Bioreductive deprotection of 4-nitrobenzyl group on thymine base in oligonucleotides for the activation of duplex formation

Saneyoshi, Hisao; Hiyoshi, Yuki; Iketani, Koichi; Kondo, Kenji; Ono, Akira

doi:10.1016/j.bmcl.2015.10.025

Cited by 18 publications

(13 citation statements)

References 22 publications

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“…In this nucleobase, the stimulus‐responsive moiety was employed as a protecting group for the efficient construction of the desired oligonucleotides . For more bio‐relevant applications, nitro‐aromatic groups have been introduced at O 4 of thymine, phosphonate backbones or hydroxyl groups of ribose in oligonucleotides, for exploring reduction‐responsive oligonucleotides. In another example of a reduction‐responsive unit, a methyldithiomethyl group was introduced at the 2′‐hydroxyl group of ribose .…”

Section: Figurementioning

confidence: 99%

“…Various groups, including ours, have recently developed biomolecules bearing a 4‐nitrobenzyl (NB) group as a reduction stimulus‐responsive unit . Here, we extended the strategy to nucleic acids for developing reduction‐responsive oligonucleotides exhibiting discrete secondary‐structure transitions, by introducing the NB group into a nucleobase at a specific site of the nucleic acid.…”

Section: Figurementioning

confidence: 99%

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Reduction‐Responsive Guanine Incorporated into G‐Quadruplex‐Forming DNA

et al. 2016

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Stimulus-responsive biomolecules are attractive targets to understand biomolecule behaviour as well as to explore their therapeutic and diagnostic applications. We demonstrate that a reduction-responsive cleavable group (chemically caged unit) introduced into the guanine ring enables modulation of the secondary structure transition of an oligonucleotide in a reduction-responsive and traceless manner leaving the unmodified oligonucleotide of interest. This simple but robust strategy could yield a variety of stimuli-responsive oligonucleotides.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Reduction‐Responsive Guanine Incorporated into G‐Quadruplex‐Forming DNA

et al. 2016

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“…Hypoxic conditions that are characteristic of solid tumors represent a remarkable stimulus to convert non-active prodrugs into active drugs under reductase action. Three examples of hypoxia-activated ONs have been reported thus far, with a hypoxia-labile modification either in the phosphate backbone to mask the negative charge and provide better tumor selectivity [ 25 – 26 ] or at the nucleobase to modulate the hybridization properties with the target [ 27 ]. In all cases, a nitro-derivative-modified thymidine phosphoramidite was prepared and incorporated into oligothymidylates (dT) n or heterosequences at different sites.…”

Section: Reviewmentioning

confidence: 99%

“…Modifications at the nucleobase: The third example reported by Saneyoshi and Ono refers to ONs containing the hypoxia-labile group on the nucleobase. It was shown that (dT) 5 with one 4-nitrobenzylthymine was deprotected in vitro by nitroreductase in the presence of NADH to produce (dT) 5 with native thymine ( Scheme 6 ) [ 27 ]. In addition, thermal stabilities of the duplexes formed with thymine-modified ONs and their complementary sequences were evaluated; the nucleobase modifications induced an important destabilization of the duplexes.…”

Section: Reviewmentioning

confidence: 99%

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

Debart¹,

Dupouy²,

Vasseur³

2018

Beilstein J. Org. Chem.

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Oligonucleotides (ONs) have been envisaged for therapeutic applications for more than thirty years. However, their broad use requires overcoming several hurdles such as instability in biological fluids, low cell penetration, limited tissue distribution, and off-target effects. With this aim, many chemical modifications have been introduced into ONs definitively as a means of modifying and better improving their properties as gene silencing agents and some of them have been successful. Moreover, in the search for an alternative way to make efficient ON-based drugs, the general concept of prodrugs was applied to the oligonucleotide field. A prodrug is defined as a compound that undergoes transformations in vivo to yield the parent active drug under different stimuli. The interest in stimuli-responsive ONs for gene silencing functions has been notable in recent years. The ON prodrug strategies usually help to overcome limitations of natural ONs due to their low metabolic stability and poor delivery. Nevertheless, compared to permanent ON modifications, transient modifications in prodrugs offer the opportunity to regulate ON activity as a function of stimuli acting as switches. Generally, the ON prodrug is not active until it is triggered to release an unmodified ON. However, as it will be described in some examples, the opposite effect can be sought.This review examines ON modifications in response to various stimuli. These stimuli may be internal or external to the cell, chemical (glutathione), biochemical (enzymes), or physical (heat, light). For each stimulus, the discussion has been separated into sections corresponding to the site of the modification in the nucleotide: the internucleosidic phosphate, the nucleobase, the sugar or the extremities of ONs. Moreover, the review provides a current and detailed account of stimuli-responsive ONs with the main goal of gene silencing. However, for some stimuli-responsive ONs reported in this review, no application for controlling gene expression has been shown, but a certain potential in this field could be demonstrated. Additionally, other applications in different domains have been mentioned to extend the interest in such molecules.

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“…Saneyoshi et al developed O 4 -(4-nitrobenzyl)-modified thymine (T NB , Figure 1B, a(iv)) and introduced it into DNA 13-mers. 9 They investigated the stability of DNA duplexes consisting of DNA 13-mer strands that were complementary (except for mismatch sites consisting of A against T NB pairs) before and after reduction treatment. Furthermore, as other unique examples, heat-induced removal of N-arylcarbamoyl and N-(phenylsulfonyl)carbamoyl groups from nucleobases 10a and hypoxic X-irradiation-induced removal of a 2-oxoalkyl group from thymine 10b have also been reported.…”

Section: Introduction Sites For Responsive Unitsmentioning

confidence: 99%

Chemically Caged Nucleic Acids

Ikeda

Kabumoto

2017

Chem. Lett.

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Chemically caged nucleic acids, which comprise a nucleic acid moiety and a synthetic molecular moiety (or "responsive unit") that may be removed by an appropriate chemical stimulus, are valuable for the development of nucleic acid-based therapeutic strategies like prodrugs and medicine delivery systems. Light is one such stimulus, and excellent examples of photocaged nucleic acids have been developed. However, external light sources must be used for this methodology, and this presents problems concerning light penetration and off-target cytotoxicity. In contrast, chemically caged nucleic acids, which respond to chemical stimuli and autonomously modulate their functions without the need for external stimuli, present an alternative strategy for bioapplications. Herein, recent examples of chemically caged nucleic acids are presented, and the current limitations and future challenges encountered in this field are discussed.

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Bioreductive deprotection of 4-nitrobenzyl group on thymine base in oligonucleotides for the activation of duplex formation

Cited by 18 publications

References 22 publications

Reduction‐Responsive Guanine Incorporated into G‐Quadruplex‐Forming DNA

Reduction‐Responsive Guanine Incorporated into G‐Quadruplex‐Forming DNA

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

Chemically Caged Nucleic Acids

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