Diisopropylsilyl-linked oligonucleotide analogs: solid-phase synthesis and physicochemical properties

Sardaro, Mark; Waychunas, Cheryl; Delecki, Daniel; Kruse, Lawrence I.; Kutny, Rusty; Cavanaugh, Paul F.; Yawman, A.; Upson, Donald A.

doi:10.1021/jo00079a030

Cited by 15 publications

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“…Also, additional silyl protecting groups at the 5′- and 3′-OH of nucleosides have previously been found to promote solubility in freonic solvents especially at low temperatures . Synthetic methods for silyl-linked oligonucleotides have been reported in the past. , In a typical procedure, a 5′-protected nucleoside is 3′-silylated with a silylating reagent and a base. Finally, this silyl-linked nucleoside continues to react with a second 3′-protected nucleoside to produce a fully protected 3′,5′-silyl-linked dinucleotide.…”

Section: Resultsmentioning

confidence: 99%

Base−Base Recognition of Nonionic Dinucleotide Analogues in an Apolar Environment Studied by Low-Temperature NMR Spectroscopy

Xiao

Weisz

2010

J. Am. Chem. Soc.

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Two self-complementary dinucleotide analogues T(Si)A and A(Si)T with a nonionic diisopropylsilyl-modified backbone were synthesized, and their association in a nonaqueous aprotic environment was studied by NMR spectroscopy. Using a CDClF(2)/CDF(3) solvent mixture, measurements at temperatures as low as 113 K allowed the observation and structural characterization of individual complexes in the slow exchange regime. The A(Si)T analogue associates to exclusively form a dinucleotide antiparallel duplex with regular Watson-Crick base pairing, but both A and T nucleosides exhibit a predominant C3'-endo sugar pucker reminiscent of an A-type conformation. In contrast to A(Si)T, the T(Si)A dinucleotide is found to exhibit significant variability and flexibility. Thus, different secondary structures with weaker hydrogen bonds for all T(Si)A structures are observed at low temperatures. Although a B-like Watson-Crick antiparallel dinucleotide duplex with a preferred C2'-endo sugar pucker largely predominates at temperatures above 153 K, two additional species, namely a dinucleotide Hoogsteen duplex with a syn glycosidic torsion angle of the adenosine nucleoside and a presumably intramolecularly folded structure, are increasingly populated upon further cooling. By adding typical DNA intercalators like anthracene or benz[c]acridine derivatives to the A(Si)T dinucleotide duplex in the aprotic solvent environment, no binding of the polycyclic aromatic molecules can be detected even at lower temperatures. Obviously, van der Waals and stacking interactions are insufficient to compensate for the other unfavorable contributions to the overall free energy of binding, and only in the presence of additional hydrophobic effects in an aqueous environment does binding occur.

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Section: Resultsmentioning

confidence: 99%

Base−Base Recognition of Nonionic Dinucleotide Analogues in an Apolar Environment Studied by Low-Temperature NMR Spectroscopy

Xiao

Weisz

2010

J. Am. Chem. Soc.

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“…There are also morpholinos with carbamate linkages [ 138 ]. Dialkylsilyl oligonucleotides are acid sensitive and have very low water solubility [ 139 , 140 ].…”

Section: Artificial Nucleic Acidsmentioning

confidence: 99%

The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides

Bege

Borbás

2022

Pharmaceuticals

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Nucleic acids play a central role in human biology, making them suitable and attractive tools for therapeutic applications. While conventional drugs generally target proteins and induce transient therapeutic effects, nucleic acid medicines can achieve long-lasting or curative effects by targeting the genetic bases of diseases. However, native oligonucleotides are characterized by low in vivo stability due to nuclease sensitivity and unfavourable physicochemical properties due to their polyanionic nature, which are obstacles to their therapeutic use. A myriad of synthetic oligonucleotides have been prepared in the last few decades and it has been shown that proper chemical modifications to either the nucleobase, the ribofuranose unit or the phosphate backbone can protect the nucleic acids from degradation, enable efficient cellular uptake and target localization ensuring the efficiency of the oligonucleotide-based therapy. In this review, we present a summary of structure and properties of artificial nucleic acids containing nucleobase, sugar or backbone modifications, and provide an overview of the structure and mechanism of action of approved oligonucleotide drugs including gene silencing agents, aptamers and mRNA vaccines.

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“…Our strategy uses a bis(hydroxymethyl)silicon chain in order to improve the overall lipophily of the resulting ODN and to take advantage of the wide range of reactions permitted by silicon. So far, silicon has been seldom used in ODN analogues synthesis, except for alkoxysilane internucleoside linkage, but the known sensitivity of the alkoxysilane moiety to both acids and bases restricts its use in vivo . In our work, a silicon atom replaced carbon-4‘ of the deoxyribose, while carbon-2‘ and the carbohydrate oxygen were removed; finally, to avoid potential β-elimination during the course of the synthesis, a propyl chain (instead of an ethyl) separates the heterocyclic base from silicon (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Silicon Analogues of Acyclonucleotides Incorporable in Oligonucleotide Solid-Phase Synthesis

1997

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The synthesis of the four silicon analogues of acyclonucleosides was described. In every case, the silicon atom was introduced onto an allyl group on the natural nucleobase following a hydrosilylation reaction. Diols obtained were protected as 4,4′-dimethoxytrityl ethers and subsequently activated as 2-cyanoethyl N,N-diisopropylchlorophosphoramidite in order to be suitable for oligonucleotide solid phase synthesis.

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Diisopropylsilyl-linked oligonucleotide analogs: solid-phase synthesis and physicochemical properties

Cited by 15 publications

References 0 publications

Base−Base Recognition of Nonionic Dinucleotide Analogues in an Apolar Environment Studied by Low-Temperature NMR Spectroscopy

Base−Base Recognition of Nonionic Dinucleotide Analogues in an Apolar Environment Studied by Low-Temperature NMR Spectroscopy

The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides

Synthesis of Silicon Analogues of Acyclonucleotides Incorporable in Oligonucleotide Solid-Phase Synthesis

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