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Characterization of high molecular weight impurities in synthetic phosphorothioate oligonucleotides.
Phosphorothioate oligonucleotides manufactured by standard phosphoramidite techniques using 2'-deoxyadenosine- or 2'-O-(2-methoxyethyl)-5-methylcytosine-loaded solid supports contain branched impurities, but these impurities are not produced when a universal, non-nucleoside derivatized support is used. Expand
Synthesis of High-Quality Antisense Drugs. Addition of Acrylonitrile to Phosphorothioate Oligonucleotides: Adduct Characterization and Avoidance
It is demonstrated that the acrylonitrile (AN) generated during the ammonolysis step of oligonucleotide manufacture selectively adds to thymine residue present in ISIS 2302 to give a full-lengthExpand
Recognition of GC base pairs by triplex forming oligonucleotides containing nucleosides derived from 2-aminopyridine.
It is found that for the beta-anomer of AP, the complex between (AP)6T6and the target site G6A6*T6C6 is stable, generating a clear DNase I footprint at oligonucleotide concentrations as low as 0.25 microM at pH 5.0, in contrast to 50 microM C6T 6 which has no effect on the cleavage pattern. Expand
Use of the 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl (Fpmp) and related protecting groups in oligoribonucleotide synthesis: stability of internucleotide linkages to aqueous acid.
It is concluded that Fpmp is a suitable 2'-protecting group even in the synthesis of particularly acid-sensitive sequences as it is demonstrated that the rate of acid-catalyzed hydrolysis of the internucleotide linkages of oligoribonucleotides is sequence dependent. Expand
Formation of 4,4'-dimethoxytrityl-C-phosphonate oligonucleotides.
Incomplete sulfurization during solid-phase synthesis of phosphorothioate oligonucleotides using phosphoramidite chemistry was identified as the cause of formation of two new classes ofExpand
Pyridinium Trifluoroacetate/N-Methylimidazole as an Efficient Activator for Oligonucleotide Synthesis via the Phosphoramidite Method
A new activator is reported for coupling phosphoramidites to a free 5‘-hydroxyl group during oligonucleotide synthesis. Pyridinium trifluoroacetate/N-methyl imidazole is a remarkably efficientExpand
Efficient triple helix formation by oligodeoxyribonucleotides containing alpha- or beta-2-amino-5-(2-deoxy-D-ribofuranosyl) pyridine residues.
Molecular modelling studies showed that an alpha-anomeric AP nucleotide can be accommodated within an otherwise beta-anomersic triplex with only minor perturbation of the triplex structure, and the lack of a differential stability between alpha-AP- and beta- AP-containing triplexes at pH >7, predicted from the behaviour of the B- type models, suggests that the A-type models are more appropriate. Expand
Synthesis of Antisense Oligonucleotides: Replacement of 3H-1,2-Benzodithiol-3-one 1,1-Dioxide (Beaucage Reagent) with Phenylacetyl Disulfide (PADS) As Efficient Sulfurization Reagent: From Bench to
It is demonstrated that phosphorothioate oligodeoxyribonucleotides can be synthesized on scales from 1 μmol to 150 mmol using phenylacetyl disulfide (PADS) as an efficient and economical replacemen...
Impurities in Oligonucleotide Drug Substances and Drug Products.
Reporting, identification, and qualification thresholds suitable for product-related impurities of therapeutic oligonucleotides are proposed and chemistry and safety aspects are considered. Expand