Synthesis of hexanucleotide analogues containing diisopropylsilyl internucleotide linkages

Cormier, James F.; Ogilvie, Kevin

doi:10.1093/nar/16.10.4583

Cited by 36 publications

(7 citation statements)

References 8 publications

(3 reference statements)

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“…Snake-venom phosphodiesterase, a 3'-exonuclease which is known to cleave both 3',5'and 2',5'-phosphodiester bonds, completely degraded 2',5'-r(Ap)9A, 3' ,5'/2' ,5'-r(Ap)9A, 2' ,5'-r(Up)9U and 2',5'-r(Cp)9C to nucleoside 5'-monophosphates (HPLC). Nuclease S1 hydrolyzed 2',5'-r(Ap)gA to the extent of 50% after 30 min at 37°C whereas 3',5'-r(Ap)gA was completely hydrolyzed within 5 (Table 2) and the solution was transferred Table 1. Oligonucleotides prepared for binding studies Ali;annplen*tide Sn.nic Normal 3',S'-linked oligomers 5-r(AAA AAA AAA A) 2',5'-linked fragments base stack more readily than the corresponding 3',5'-linked isomers (24).…”

Section: Resultsmentioning

confidence: 99%

Oligoribonucleotides containing 2′,5′-phosphodiester linkages exhibit binding selectivity for 3′,5′-RNA over 3′,5′-ssDNA

1993

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Oligoribonucleotides containing 2',5'-phosphodiester linkages have been synthesized on a solid support by the 'silyl-phosphoramidite' method. The stability of complexes formed between these oligonucleotides and complementary 3',5'-RNA strands have been studied using oligoadenylates and a variety of oligonucleotides of mixed base sequences including phosphorothioate backbones. In many cases, particularly for 2',5'-linked adenylates, the UV melting profiles are quite sharp and exhibit large hyperchromic changes. Substituting a few 3',5'-linkages with the 2',5'-linkage within an oligomer lowers the Tm of the complex and the degree of destabilization depends on the neighboring residues and neighboring linkages. The 2',5'-linked oligoribonucleotides prepared in this study exhibited remarkable selectivity for complementary single stranded RNA over DNA. For example, in 0.01 M phosphate buffer -0.10 M NaCI (pH 7.0), no association was observed between 2',5'-r(CCC UCU CCC UUC U) and its Watson -Crick DNA complement 3',5'-d(AGAAGGGAGAGGG). However, 2',5'-r(CCC UCU CCC UUC U) with its RNA complement 3',5'-r(AGAAGGGAGAGGG) forms a duplex which melts at 400C. The decamer 2',5'-r(Ap)gA forms a complex with both poly dT and poly rU but the complex [2',5'-r(Ap)9A]:[poly dT] is unstable (Tm, -1 OC) and is seen only at high salt concentrations. In view of their unnatural character and remarkable selectivity for single stranded RNA, 2',5'-oligo-RNAs and their derivatives may find use as selective inhibitors of viral mRNA translation, and as affinity ligands for the purification of cellular RNA.

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Section: Resultsmentioning

confidence: 99%

Oligoribonucleotides containing 2′,5′-phosphodiester linkages exhibit binding selectivity for 3′,5′-RNA over 3′,5′-ssDNA

1993

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“…Considerations of synthetic feasability and hydrolytic stability led us away from moieties containing silicon directly bonded to four oxygen atoms, so we chose instead to pursue analogs containing dialkylsiloxane residues, where the alkyl groups could be selected to modulate linker stability and polarity, with the constraint that both alkyl groups must be identical to render the resulting phosphate mimic achiral. While our work was ongoing, similar efforts to prepare silicon-based OAs were reported by other laboratories (5)(6).…”

Section: Silicon-based Noasmentioning

confidence: 60%

Synthesis of Nonionic Oligonucleotide Analogues

Maddry

Reynolds

Secrist

1994

ACS Symposium Series

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The design and synthesis of several classes of oligonucleotide analogs (OAs) incorporating improved, achiral, non-ionic phosphate linker surrogates are reported. Specifically, the synthesis and properties of monomers and oligomers based on five such linkers will be described, including lipophilic linkers based on various dialkylsiloxane moieties, especially diisopropylsiloxane; two moderately polar linkers (carboxylate ester and carboxamide) based on the appropriately 3'-substituted (hydroxy and amino), 5'-doubly-homologated nucleoside carboxylic acids; and polar surrogates (sulfonate esters and amides) prepared from the 3'-substituted, 5'-homologated nucleoside sulfonic acids. The potential advantages of oligonucleotides bearing non-ionic backbone linkages as clinical therapeutic agents are briefly discussed.The enormous potential of antisense oligonucleotide analogs (OAs) for the treatment of disease has elicited great excitement among medicinal chemists, who are intrigued by their promise of high specificity and broad applicability. The major goal of this strategy is to inhibit gene expression by interference with the transcription, translation, or replication of a given gene, through complementary (normally Watson-Crick) hybridization between the target (sense) and OA (antisense) strands. This interest has prompted extensive research designed to improve the stability, bioavailability, and potency of OAs. Our interest in this area arose from the observation that the current generation of OAs suffered from several shortcomings that might ultimately preclude their introduction as clinically useful agents. Thus, antisense compounds composed of natural DNA or RNA sequences suffer from rapid enzymatic degradation and poor uptake; DNA analogs based on the phosphorothioate linker, while of improved stability, nonetheless are charged, resulting in inefficient cellular membrane permeability and rapid clearance from the plasma, and chiral, which can cause intractable purification problems; and methylphosphonates, though uncharged, still suffer from the chirality drawback and typically display low potency. It was our belief that useful drugs would emerge only through the use of achiral, non-ionic OAs (NOAs). Consequently, we embarked upon a program of design and synthesis to

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“…An internucleotide diisopropylsilyl linkage was chosen as a neutral phosphodiester analogue based on its favorable stability and reactivity. 7 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. 8 Synthetic methods for silyl-linked oligonucleotides have been reported in the past.…”

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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Synthesis of hexanucleotide analogues containing diisopropylsilyl internucleotide linkages

Abstract: The synthesis of two silyl-linked hexanucleotide analogues is described. Hypochromicity and CD measurements indicate that the thymidine hexanucleotide analogue bears a strong resemblance to its phosphodiester-linked counterpart.

Cited by 36 publications

References 8 publications

Oligoribonucleotides containing 2′,5′-phosphodiester linkages exhibit binding selectivity for 3′,5′-RNA over 3′,5′-ssDNA

Oligoribonucleotides containing 2′,5′-phosphodiester linkages exhibit binding selectivity for 3′,5′-RNA over 3′,5′-ssDNA

Synthesis of Nonionic Oligonucleotide Analogues

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

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