Synthesis of N-substituted hydroxyprolinol phosphoramidites for the preparation of combinatorial libraries

Hébert, Normand; Davis, Peter W.; Debaets, Elizabeth; Acevedo, Oscar L.

doi:10.1016/0040-4039(94)88498-6

Cited by 31 publications

(25 citation statements)

References 8 publications

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“…The structures and nucleotide sequences of the oligomers used in this study are given in Figure 1 . While planning the synthesis of oligonucleotides with non-nucleoside units bearing dodecyl chains, we considered that the free terminal hydroxyethyl group of this unit can cause degradation of the modified oligonucleotide during the deprotection step in basic aqueous solutions [ 40 , 41 ]. Therefore, we added an extra thymidylate unit at 3′- (FAM-17-D ( Figure S3 )) or 5′-end (D-13, D-13 PG , D-17, D-17 PG , D-17-FAM ( Figure S4 ), D-22 PG ) of corresponding oligomers to overcome this problem.…”

Section: Resultsmentioning

confidence: 99%

Amphiphilic “Like-A-Brush” Oligonucleotide Conjugates with Three Dodecyl Chains: Self-Assembly Features of Novel Scaffold Compounds for Nucleic Acids Delivery

et al. 2020

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The conjugation of lipophilic groups to oligonucleotides is a promising approach for improving nucleic acid-based therapeutics’ intracellular delivery. Lipid oligonucleotide conjugates can self-aggregate in aqueous solution, which gains much attention due to the formation of micellar particles suitable for cell endocytosis. Here, we describe self-association features of novel “like-a-brush” oligonucleotide conjugates bearing three dodecyl chains. The self-assembly of the conjugates into 30–170 nm micellar particles with a high tendency to aggregate was shown using dynamic light scattering (DLS), atomic force (AFM), and transmission electron (TEM) microscopies. Fluorescently labeled conjugates demonstrated significant quenching of fluorescence intensity (up to 90%) under micelle formation conditions. The conjugates possess increased binding affinity to serum albumin as compared with free oligonucleotides. The dodecyl oligonucleotide conjugate and its duplex efficiently internalized and accumulated into HepG2 cells’ cytoplasm without any transfection agent. It was shown that the addition of serum albumin or fetal bovine serum to the medium decreased oligonucleotide uptake efficacy (by 22.5–36%) but did not completely inhibit cell penetration. The obtained results allow considering dodecyl-containing oligonucleotides as scaffold compounds for engineering nucleic acid delivery vehicles.

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Section: Resultsmentioning

confidence: 99%

Amphiphilic “Like-A-Brush” Oligonucleotide Conjugates with Three Dodecyl Chains: Self-Assembly Features of Novel Scaffold Compounds for Nucleic Acids Delivery

et al. 2020

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“…To synthesize and evaluate siRNA–GalNAc conjugates containing ligand motifs 2 and 3 (Figure 1), building blocks 6 and 10 , with a single GalNAc moiety, and the corresponding phosphoramidites 7 and 11 and solid supports 8 and 12 were synthesized as shown in Scheme . Carboxylic acid 4 from D ‐(+)‐galactosamine and amine 5 from (3 R ,5 S )‐5‐[[bis(4‐methoxyphenyl)phenylmethoxy]methyl]‐3‐pyrrolidinol15 ( 9 ) were synthesized according to published procedures from our laboratory 5. Activation of carboxylic acid 4 with N , N , N′ , N′ ‐tetramethyl‐ O ‐(benzotriazol‐1‐yl)uronium hexafluorophosphate (HBTU) in the presence of diisopropylethylamine (DIEA) in dichloromethane, followed by treatment with amine 5 , afforded compound 6 .…”

Section: Methodsmentioning

confidence: 99%

Hepatocyte‐Specific Delivery of siRNAs Conjugated to Novel Non‐nucleosidic Trivalent N‐Acetylgalactosamine Elicits Robust Gene Silencing in Vivo

et al. 2015

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We recently demonstrated that siRNAs conjugated to triantennary N-acetylgalactosamine (GalNAc) induce robust RNAi-mediated gene silencing in the liver, owing to uptake mediated by the asialoglycoprotein receptor (ASGPR). Novel monovalent GalNAc units, based on a non-nucleosidic linker, were developed to yield simplified trivalent GalNAc-conjugated oligonucleotides under solid-phase synthesis conditions. Synthesis of oligonucleotide conjugates using monovalent GalNAc building blocks required fewer synthetic steps compared to the previously optimized triantennary GalNAc construct. The redesigned trivalent GalNAc ligand maintained optimal valency, spatial orientation, and distance between the sugar moieties for proper recognition by ASGPR. siRNA conjugates were synthesized by sequential covalent attachment of the trivalent GalNAc to the 3'-end of the sense strand and resulted in a conjugate with in vitro and in vivo potency similar to that of the parent trivalent GalNAc conjugate design.

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“…Compounds 4a and b were reacted with substituted phthalic anhydrides in the presence of AlCl 3 to give the benzophenones 5 , which were reacted with the resorcinol analogs 6 ( a – c ) in trifluoroacetic acid/methanesulfonic acid to yield the carboxyethyl substituted dyes 7 . Treatment of compounds 7 with trifluoroacetic anhydride generated lactones 8 , which were first reacted with the DMT-protected hydroxyprolinol 9 ( 21 ) and then with trimethylacetic anhydride to afford the protected dyes 10 . Reaction of intermediates 10 first with succinic anhydride and then with pentafluorophenyl trifluoroacetate, yielded the PFP esters 11 .…”

Section: Methodsmentioning

confidence: 99%

A novel endonuclease IV post-PCR genotyping system

Kutyavin¹,

Milesi²,

Belousov³

et al. 2006

Nucleic Acids Research

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Here we describe a novel endonuclease IV (Endo IV) based assay utilizing a substrate that mimics the abasic lesions that normally occur in double-stranded DNA. The three component substrate is characterized by single-stranded DNA target, an oligonucleotide probe, separated from a helper oligonucleotide by a one base gap. The oligonucleotide probe contains a non-fluorescent quencher at the 5′ end and fluorophore attached to the 3′ end through a special rigid linker. Fluorescence of the oligonucleotide probe is efficiently quenched by the interaction of terminal dye and quencher when not hybridized. Upon hybridization of the oligonucleotide probe and helper probe to their complementary target, the phosphodiester linkage between the rigid linker and the 3′ end of the probe is efficiently cleaved, generating a fluorescent signal. In this study, the use of the Endo IV assay as a post-PCR amplification detection system is demonstrated. High sensitivity and specificity are illustrated using single nucleotide polymorphism detection.

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Synthesis of N-substituted hydroxyprolinol phosphoramidites for the preparation of combinatorial libraries

Cited by 31 publications

References 8 publications

Amphiphilic “Like-A-Brush” Oligonucleotide Conjugates with Three Dodecyl Chains: Self-Assembly Features of Novel Scaffold Compounds for Nucleic Acids Delivery

Amphiphilic “Like-A-Brush” Oligonucleotide Conjugates with Three Dodecyl Chains: Self-Assembly Features of Novel Scaffold Compounds for Nucleic Acids Delivery

Hepatocyte‐Specific Delivery of siRNAs Conjugated to Novel Non‐nucleosidic Trivalent N‐Acetylgalactosamine Elicits Robust Gene Silencing in Vivo

A novel endonuclease IV post-PCR genotyping system

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