2‐[(Acetyloxy)methyl]‐4‐(acetylsulfanyl)‐2‐(ethoxycarbonyl)‐3‐oxobutyl Group: A Thermolabile Protecting Group for Phosphodiesters

Kiuru, Emilia; Lönnberg, Harri; Ora, Mikko

doi:10.1002/hlca.201300028

Cited by 4 publications

(4 citation statements)

References 10 publications

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“…Compared to esters, thioesters are more prone to amine nucleophiles undergoing a nucleophilic displacement of the acyl group [17,18] . After that the exposed thiol group attacks on the C1 releasing the phosphodiester.…”

Section: Resultsmentioning

confidence: 99%

“…Table 3 records the results obtained. Compared to esters, thioesters are more prone to amine nucleophiles undergoing a nucleophilic displacement of the acyl group. [17,18] After that the exposed thiol group attacks on the C1 releasing the phosphodiester. In a mixture of anhydrous 5 % piperidine in acetonitrile, the phosphotriester 1 was converted to the phosphodiester 1** with a half-life of 13 min.…”

Section: Stability Of the Phosphotriesters 1 2 And 5 In Non-aqueous mentioning

confidence: 99%

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Stability of the Phosphotriester PDE6D Inhibitors

et al. 2021

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The kinetics for the cleavage of the phosphotriester PDE6D inhibitors 1 (Deltaflexin‐2) and 3 (Deltaflexin‐1) and their derivatives 2, 4 and 5 is presented under various conditions in aqueous solutions. The conversion of the phosphotriesters (1–5) into the phosphodiesters 1**–5** was detected to take place as a major degradation process. In the absence of enzyme, the 4‐acetylthio‐2,2‐dimethyl‐3‐oxobutyl protected compounds (1, 4 and 5) are one order of magnitude more stable than the 4‐acetylthio‐2‐ethoxycarbonyl‐3‐oxo‐2‐methylbutyl protected ones (2 and 3). In cell culture (DMEM) containing fetal bovine serum and l‐glutamine, an intermediary formation of S−S‐dimer competed with the removal of the protecting group after deacetylation of the starting material. In addition, the susceptibility of the compounds to amine nucleophiles as well as their stability under acidic and basic condition were determined in non‐aqueous solutions.

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Section: Resultsmentioning

confidence: 99%

Section: Stability Of the Phosphotriesters 1 2 And 5 In Non-aqueous mentioning

confidence: 99%

Stability of the Phosphotriester PDE6D Inhibitors

et al. 2021

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“…Finally, it should be mentioned that additional thermolabile protecting groups for phosphodiesters have been reported by Lönnberg [ 63 – 64 ]. Actually, in the search for esterase-labile protecting groups for phosphoesters, a set of 2,2-disubstituted 4-acylthio-3-oxobutyl groups was additionally thermolabile.…”

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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“…TPGs were proposed as a protection of the phosphate function where a temperature‐dependent group constitutes a good alternative for the commonly used cyanoethyl group. Although 2‐( N ‐formyl‐ N ‐methyl)aminoethyl, 3‐( N ‐tert‐butylcarboxamido)‐1‐propyl (Wilk et al, , ), 3‐(2‐pyridyl)‐1‐propyl (Cieślak and Beaucage, ), 4‐methylthio‐1‐butyl (Cieslak et al., ), 2‐Acetyloxymethyl‐4‐acetylthio‐2‐ethoxycarbonyl‐3‐oxobutyl (Kiuru et al., ), and 2‐benzylamideethyl (Guzaev and Manoharan, ) groups have different thermal stability, their usefulness in protection of the phosphate function during nucleic acid synthesis has been proven. Particularly noteworthy is the 4‐oxopenthyl (Wilk et al., ) group that is removed in the thermolytic or basic conditions and it can be completely released from the protected part in a molecule within only 30 min.…”

Section: Commentarymentioning

confidence: 99%

2‐Pyridinyl Thermolabile Groups as General Protectants for Hydroxyl, Phosphate, and Carboxyl Functions

Brzezinska

Witkowska

Kaczyński

et al. 2017

CP Nucleic Acid Chemistry

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Application of 2-pyridinyl thermolabile protecting groups (2-PyTPGs) for protection of hydroxyl, phosphate, and carboxyl functions is presented in this unit. Their characteristic feature is a unique removal process following the intramolecular cyclization mechanism and induced only by temperature rise. Deprotection rate of 2-PyTPGs is dependent on certain parameters, such as solvent (aqueous or non-aqueous medium), pH values, and electron distribution in a pyridine ring. The presented approach pertains not only to protecting groups but also to an advanced system of controlling certain properties of 2-pyridinyl derivatives. We improved the "chemical switch" method, allowing us to regulate the protecting group stability by inversing the electron distribution in 2-PyTPG. Together with pH values manipulation, this allows us to regulate the protecting group stability. Moreover, phosphite cyclization to oxazaphospholidine provides a very stable but easily reversible tool for phosphate protection/modifications. For all TPGs we confirmed their utility in a system of protecting groups. This concept can contribute to designing the general protecting group that could be useful in bioorganic chemistry. © 2017 by John Wiley & Sons, Inc.

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2‐[(Acetyloxy)methyl]‐4‐(acetylsulfanyl)‐2‐(ethoxycarbonyl)‐3‐oxobutyl Group: A Thermolabile Protecting Group for Phosphodiesters

Abstract: The potential of the protecting group in compound (IV) as an esterase‐ and thermolabile group is studied.

Cited by 4 publications

References 10 publications

Stability of the Phosphotriester PDE6D Inhibitors

Stability of the Phosphotriester PDE6D Inhibitors

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

2‐Pyridinyl Thermolabile Groups as General Protectants for Hydroxyl, Phosphate, and Carboxyl Functions

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