Synthesis, Dynamic Combinatorial Chemistry, and PCR Amplification of 3′–5′ and 3′–6′ Disulfide‐linked Oligonucleotides

Hansen, Dennis J.; Manuguerra, Ilenia; Kjelstrup, Michael Brøndum; Gothelf, Kurt V.

doi:10.1002/ange.201405761

Cited by 8 publications

(4 citation statements)

References 28 publications

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“…In cell‐penetrating poly(disulfide)s (CPDs) such as 2 ,[7] the peptide backbone of CPPs is replaced by a disulfide polymer [8 – 13]. This is of interest to i ) prepare the transporters in situ by ring‐opening disulfide‐exchange polymerization,[7] ii ) destroy the transporters upon arrival in the cytosol by reductive depolymerization to minimize toxicity and liberate the native substrate,[8] and iii ) integrate new uptake mechanisms ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Sidechain Engineering in Cell‐Penetrating Poly(disulfide)s

Morelli

Matile

2017

Helvetica Chimica Acta

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Cell‐penetrating poly(disulfide)s (CPDs) have been introduced recently to explore new ways to enter into cells. In this report, we disclose a general method to covalently modify the sidechains of CPDs. Compatibility of copper‐catalyzed alkyne‐azide cycloaddition (CuAAC) with the addition of either strained cyclic disulfides of varied ring tension or increasing numbers of guanidinium and phosphonium cations is demonstrated. Reloading CPDs with disulfide ring tension results in an at least 20‐fold increase in activity with preserved sensitivity toward inhibition with the Ellman's reagent. The cumulation of permanent positive charges by sidechain engineering affords Ellman‐insensitive CPDs with similarly increased activity. Co‐localization experiments indicate that the CPDs reach endosomes, cytosol and nucleus, depending on their nature and their concentration. Supported by pertinent controls, these trends confirm that CPDs operate with combination of counterion‐ and thiol‐mediated uptake, and that the balance between the two can be rationally controlled. For the most active CPDs, uptake can be observed at substrate (fluorophore) concentrations as low as 5 nm.

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Section: Introductionmentioning

confidence: 99%

Sidechain Engineering in Cell‐Penetrating Poly(disulfide)s

Morelli

Matile

2017

Helvetica Chimica Acta

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“… 18 A detailed study revealed several molecular characteristics of artificial backbones that are required for compatibility with DNA polymerases during replication. 19 Such polymerase compatible artificial backbones comprise 5′- S -phosphorothioesters, 20 phosphorothioates, 21 disulfides, 22 boranophosphates, 23 phosphoramidates, 10 , 24 , 25 amides, 19 , 26 ureas, 18 squaramides, 18 and triazoles. 8 , 9 , 19 , 27 − 29 Among these, the triazole linkage (TL) represents a powerful and versatile chemical moiety that can be readily formed by the Cu I -catalyzed azide–alkyne cycloaddition (CuAAC) reaction, resulting in 1,4-disubstituted 1,2,3-triazoles.…”

Section: Introductionmentioning

confidence: 99%

A New 1,5-Disubstituted Triazole DNA Backbone Mimic with Enhanced Polymerase Compatibility

et al. 2021

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Triazole linkages (TLs) are mimics of the phosphodiester bond in oligonucleotides with applications in synthetic biology and biotechnology. Here we report the RuAAC-catalyzed synthesis of a novel 1,5-disubstituted triazole (TL 2 ) dinucleoside phosphoramidite as well as its incorporation into oligonucleotides and compare its DNA polymerase replication competency with other TL analogues. We demonstrate that TL 2 has superior replication kinetics to these analogues and is accurately replicated by polymerases. Derived structure–biocompatibility relationships show that linker length and the orientation of a hydrogen bond acceptor are critical and provide further guidance for the rational design of artificial biocompatible nucleic acid backbones.

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“…For instance, π stacking can enhance the catalytic activity of complexes containing a pyrene moiety; 34 rational ligand design 35,36 or by a wise choice of the counterion. 37−43 Indeed, the interplay between covalent and noncovalent interactions recently led to interesting results in dynamic combinatorial library-driven synthesis 44−46 (also applied to biomolecules 47,48 ), surface chemistry, 49,50 and reactivity of halogen-containing moieties. 51 More specifically, the presence of a noncovalent interaction can influence the covalency of a chemical bond.…”

Section: ■ Introductionmentioning

confidence: 99%

Interplay between Gold(I)-Ligand Bond Components and Hydrogen Bonding: A Combined Experimental/Computational Study

2019

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The influence of weak interactions on the donation/back-donation bond components in the complex [(NHC)Au( SeU )] + (NHC = N-heterocyclic carbene; SeU = selenourea) has been studied by coupling experimental and theoretical techniques. In particular, NMR 1 H and pulsed-field gradient spin-echo titrations allowed us to characterize the hydrogen bond (HB) between the −NH 2 moieties of SeU and the anions PF 6 – and ClO 4 – , whereas 77 Se NMR spectroscopy allowed us to characterize the Au–Se bond. Theoretically, the Au–Se and Au–C orbital interactions have been decomposed using the natural orbital for the chemical valence framework and the bond components quantified through the charge displacement analysis. This methodology provides the quantification of the Dewar–Chatt–Duncanson (DCD) components for the Au–C and Au–Se bonds in the absence and presence of the second-sphere HB. The results presented here show that the anion has a dual mode action: it modifies the conformation of the cation by ion pairing (and this already influences the DCD components) and it induces new polarization effects that depend on the relative anion/cation relative orientation. The perchlorate polarizes SeU , enhancing the Se → Au σ donation and the Au → C back-donation and depressing the C → Au σ donation. On the contrary, the hexafluorophosphate depresses both the Se → Au and C → Au σ donations.

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Synthesis, Dynamic Combinatorial Chemistry, and PCR Amplification of 3′–5′ and 3′–6′ Disulfide‐linked Oligonucleotides

Cited by 8 publications

References 28 publications

Sidechain Engineering in Cell‐Penetrating Poly(disulfide)s

Sidechain Engineering in Cell‐Penetrating Poly(disulfide)s

A New 1,5-Disubstituted Triazole DNA Backbone Mimic with Enhanced Polymerase Compatibility

Interplay between Gold(I)-Ligand Bond Components and Hydrogen Bonding: A Combined Experimental/Computational Study

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