Synthesis, binding, nuclease resistance and cellular uptake properties of 2′- O -acetalester-modified oligonucleotides containing cationic groups

Biscans, Annabelle; Rouanet, Sonia; Bertrand, Jean-Rémi; Vasseur, Jean‐Jacques; Dupouy, Christelle; Debart, Françoise

doi:10.1016/j.bmc.2015.07.054

Cited by 10 publications

(10 citation statements)

References 40 publications

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“…52–53 Analogous to OMP prodrug 4 , this compound would release the parent drug and an equivalent of formaldehyde upon bioactivation by esterases. To synthesize this compound, (3 S ,4 R )- 3 was prepared as a single enantiomer from levcromakalim by the same method that was used to obtain racemic 3 from cromakalim (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

Analogs of the ATP-Sensitive Potassium (K_ATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity

et al. 2016

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KATP channel openers have emerged as potential therapeutics for the treatment of glaucoma, lowering intraocular pressure in animal models and cultured human anterior segments. We have prepared water soluble phosphate and dipeptide derivatives of the KATP channel opener cromakalim and evaluated their IOP lowering capabilities in vivo. In general, the phosphate derivatives proved to be more chemically robust and efficacious at lowering IOP with once daily dosing in a normotensive mouse model. Two of these phosphate derivatives were further evaluated in a normotensive rabbit model, with a significant difference in activity observed. No toxic effects on cell structure or alterations in morphology of the aqueous humor outflow pathway were observed after treatment with the most efficacious compound (3S,4R)−2, suggesting that it is a strong candidate for development as an ocular hypotensive agent.

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Section: Resultsmentioning

confidence: 99%

Analogs of the ATP-Sensitive Potassium (K_ATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity

et al. 2016

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“…This difference could be explained in terms of the steric hindrance and the enhanced lipophilicityo ft he PiBuOM group,which would slow down the nuclease activity. [13] With FCS (10 %) we observed ar apid removal of the unpaired d(T) residues for siR206P iBuOM (half-life 5min). Converselyt he remainingb lunt-ended duplex in either case was stable for severalh ours ( Figure S36).…”

Section: Circular Dichroism Studiesmentioning

confidence: 83%

“…Furthermore, P i BuOM modifications protected the siRNA approximately twice as well as PivOM modifications (half‐life 28 min). This difference could be explained in terms of the steric hindrance and the enhanced lipophilicity of the P i BuOM group, which would slow down the nuclease activity …”

Section: Resultsmentioning

confidence: 99%

“…The ability of Cy3-(U PiBu ) 10 TT to cross the cellular membrane in the absence of transfection reagent was evaluated in comparison with the penetration of Cy3-U 10 TT and Cy3-(U Piv ) 10 TT. [13] A673 cells (human Ewing's sarcoma) were transfected with the three Cy3-labeled U 10 TT derivatives (50 nm and 500 nm concentration)a nd analyzed by confocal microscopy after 3hincubation in Dulbecco's modified Eagle's medium( DMEM) containing 10 %f etal calfs erum (FCS). [14] No red fluorescence was detected in the cells treated with Cy3-U 10 TT;t his confirms the lack of any capability of the natural ON to penetrate without any vectorization ( Figure 1).…”

Section: Cellular Uptakementioning

confidence: 99%

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Lipophilic 2′‐O‐Acetal Ester RNAs: Synthesis, Thermal Duplex Stability, Nuclease Resistance, Cellular Uptake, and siRNA Activity after Spontaneous Naked Delivery

et al. 2016

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The in vivo application of siRNA depends on its cellular uptake and intracellular release, and this is an unsatisfactorily resolved technical hurdle in medicinal applications. Promising concepts directed towards providing efficient cellular and intracellular delivery include lipophilic chemical modification of siRNA. Here we describe chemistry for the production of modified siRNAs designed to display improved transmembrane transport into human cells while preserving the potency of the RNAi-based inhibitors. We report the synthesis and the biochemical and biophysical characteristics of 2'-O-phenylisobutyryloxymethyl (PiBuOM)-modified siRNAs and their impact on biological activity. In the case of spontaneous cellular uptake of naked PiBuOM-modified siRNA, we observed increased target suppression in human cells relative to unmodified or pivaloyloxymethyl (PivOM)-modified siRNA. We provide evidence of improved spontaneous cellular uptake of naked PiBuOM-modified siRNA and of substantial target suppression in human cells in serum-containing medium.

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“…In this context and in extension of the previous work with the 2’- O -acetal ester modifications cited above, new modified ONs were designed with amino or guanidino-containing 2’- O -acetal ester groups bearing positive charges: 2-amino-2-methylpropionyloxymethyl (AMPrOM), 2-aminomethyl-2-ethylbutyryloxymethyl (AMEBuOM) or 2-guanidinomethyl-2-ethylbutyryloxymethyl (GMEBuOM, Fig. 3 ) [ 54 ]. The two modifications with a guanidinium and an ammonium moiety, GMEBuOM and AMPrOM, respectively, were found to be unstable during HPLC purification and handling.…”

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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Synthesis, binding, nuclease resistance and cellular uptake properties of 2′- O -acetalester-modified oligonucleotides containing cationic groups

Cited by 10 publications

References 40 publications

Analogs of the ATP-Sensitive Potassium (K_ATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity

Analogs of the ATP-Sensitive Potassium (K_ATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity

Lipophilic 2′‐O‐Acetal Ester RNAs: Synthesis, Thermal Duplex Stability, Nuclease Resistance, Cellular Uptake, and siRNA Activity after Spontaneous Naked Delivery

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

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Synthesis, binding, nuclease resistance and cellular uptake properties of 2′- O -acetalester-modified oligonucleotides containing cationic groups

Cited by 10 publications

References 40 publications

Analogs of the ATP-Sensitive Potassium (KATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity

Analogs of the ATP-Sensitive Potassium (KATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity

Lipophilic 2′‐O‐Acetal Ester RNAs: Synthesis, Thermal Duplex Stability, Nuclease Resistance, Cellular Uptake, and siRNA Activity after Spontaneous Naked Delivery

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

Contact Info

Product

Resources

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Analogs of the ATP-Sensitive Potassium (K_ATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity

Analogs of the ATP-Sensitive Potassium (K_ATP) Channel Opener Cromakalim with in Vivo Ocular Hypotensive Activity