Design, Synthesis, and Cellular Uptake of Oligonucleotides Bearing Glutathione-Labile Protecting Groups

Saneyoshi, Hisao; Ohta, Takayuki; Hiyoshi, Yuki; Saneyoshi, Takeo; Ono, Akira

doi:10.1021/acs.orglett.8b03501

Cited by 13 publications

(9 citation statements)

References 43 publications

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“… 102 While relaxed single AOCs 24 showed poor activity, 6 Abe and co-workers introduced phosphoramidite 32 for use in automated DNA and RNA synthesis. 103 − 105 Dependent on their positioning, the presence of 5–10 AOCs 32 resulted in efficient cytosolic oligonucleotide delivery. Peptide-based oligomers of COCs, together with the introduction of cell-penetrating streptavidin, also showed that multivalency of COCs strongly increases uptake.…”

Section: Privileged Scaffoldsmentioning

confidence: 99%

Thiol-Mediated Uptake

Laurent

Martinent

Lim

et al. 2021

JACS Au

111

208

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This Perspective focuses on thiol-mediated uptake, that is, the entry of substrates into cells enabled by oligochalcogenides or mimics, often disulfides, and inhibited by thiol-reactive agents. A short chronology from the initial observations in 1990 until today is followed by a summary of cell-penetrating poly(disulfide)s (CPDs) and cyclic oligochalcogenides (COCs) as privileged scaffolds in thiol-mediated uptake and inhibitors of thiol-mediated uptake as potential antivirals. In the spirit of a Perspective, the main part brings together topics that possibly could help to explain how thiol-mediated uptake really works. Extreme sulfur chemistry mostly related to COCs and their mimics, cyclic disulfides, thiosulfinates/-onates, diselenolanes, benzopolysulfanes, but also arsenics and Michael acceptors, is viewed in the context of acidity, ring tension, exchange cascades, adaptive networks, exchange affinity columns, molecular walkers, ring-opening polymerizations, and templated polymerizations. Micellar pores (or lipid ion channels) are considered, from cell-penetrating peptides and natural antibiotics to voltage sensors, and a concise gallery of membrane proteins, as possible targets of thiol-mediated uptake, is provided, including CLIC1, a thiol-reactive chloride channel; TMEM16F, a Ca-activated scramblase; EGFR, the epithelial growth factor receptor; and protein-disulfide isomerase, known from HIV entry or the transferrin receptor, a top hit in proteomics and recently identified in the cellular entry of SARS-CoV-2.

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Section: Privileged Scaffoldsmentioning

confidence: 99%

Thiol-Mediated Uptake

Laurent

Martinent

Lim

et al. 2021

JACS Au

111

208

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“…After cellular uptake, the protecting groups are deprotected by esterase or GSH to release active RNA species. − However, special synthetic procedures are needed for the preparation of these RNAs. In our laboratory, bioreduction labile protecting groups have been used for the development of reduction-activated DNA type oligonucleotides − that can be activated by the hypoxic conditions found in advanced solid tumors. , These oligonucleotides were also amenable to solid-phase DNA synthesis and purification. To expand our study into reduction-activated RNA type molecules, development of bioreduction labile 2′-hydroxyl protecting groups is critical.…”

mentioning

confidence: 99%

Development of Bioreduction Labile Protecting Groups for the 2′-Hydroxyl Group of RNA

et al. 2020

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Protection and deprotection of the 2′-hydroxyl group of RNAs are critical for RNA-based drug discovery. This paper reports development of a bioreduction labile protecting group of the 2′-hydroxyl group in RNA. After the reduction of the nitro group in a chemical or enzymatic manner, the protecting groups were removed spontaneously. The attachment of electron-donating groups to the benzene ring or benzylic carbon enabled fast and controllable deprotection of the 2′-hydroxyl protecting group under physiological conditions.

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“…Bioreduction of this type has been seen before in an E. coli NADH-dependent nitroreductase. 44 To assess the product of the reactions we followed the protocol published for a similar reductase. 45 Large-scale reactions were performed using CNR to reduce three compounds (26h, 27h, and 28h), representative of each family synthesized with the same 4-bromophenyl group.…”

mentioning

confidence: 99%

Investigating the promiscuity of the chloramphenicol nitroreductase from Haemophilus influenzae towards the reduction of 4-nitrobenzene derivatives

Green

Fosso

Mayhoub

2019

Bioorganic & Medicinal Chemistry Letters

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Chloramphenicol nitroreductase (CNR), a drug-modifying enzyme from Haemophilus influenzae, has been shown to be responsible for the conversion of the nitro group into an amine in the antibiotic chloramphenicol (CAM). Since CAM structurally bears a 4-nitrobenzene moiety, we explored the substrate promiscuity of CNR by investigating its nitroreduction of 4-nitrobenzyl derivatives. We tested twenty compounds containing a nitrobenzene core, two nitropyridines, one compound with a vinylogous nitro group, and two aliphatic nitro compounds. In addition, we also synthesized twenty-eight 4-nitrobenzyl derivatives with ether, ester, and thioether substituents and assessed the relative activity of CNR in their presence. We found several of these compounds to be modified by CNR, with the enzyme activity ranging from 1-150% when compared to CAM. This data provides insights into two areas: (i) chemoenzymatic reduction of select compounds to avoid harsh chemicals and heavy metals routinely used in reductions of nitro groups and (ii) functional groups that would aid CAM in overcoming the activity of this enzyme.

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Design, Synthesis, and Cellular Uptake of Oligonucleotides Bearing Glutathione-Labile Protecting Groups

Cited by 13 publications

References 43 publications

Thiol-Mediated Uptake

Thiol-Mediated Uptake

Development of Bioreduction Labile Protecting Groups for the 2′-Hydroxyl Group of RNA

Investigating the promiscuity of the chloramphenicol nitroreductase from Haemophilus influenzae towards the reduction of 4-nitrobenzene derivatives

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