134834-32-5Relevant articles and documents
Syntheses of Morpholine-Based Nucleotide Analogs for Hepatic siRNA Targeting and Stabilization
Hofmeister, Armin,Jahn-Hofmann, Kerstin,Brunner, Bodo,Helms, Mike W.,Metz-Weidmann, Christiane,Krack, Arne,Kurz, Michael,Li, Ziyu,Weitzenberg, Merle M.,Pflimlin, Elsa,Plettenburg, Oliver,Scheidler, Sabine
, p. 6838 - 6855 (2021)
A morpholine-based nucleotide analog was developed as a building block for hepatic siRNA targeting and stabilization. Attachment of an asialoglycoprotein-binding GalNAc ligand at the morpholine nitrogen was realized with different linkers. The obtained morpholino GalNAc scaffolds were coupled to the sense strand of a transthyretin-targeting siRNA and tested for their knockdown potency in vitro and in vivo. A clear structure-activity relationship was developed with regard to the linker type and length as well as the attachment site of the morpholino GalNAc moieties at the siRNA sense strand. Further, simple alkylation of the morpholine nitrogen led to a nucleotide analog, which increased siRNA stability, when used as a double 3′-overhang at the sense strand sequence. Combination of the best morpholino GalNAc building blocks as targeting nucleotides with an optimized stabilizing alkyl-substituted morpholine as 3′-overhangs resulted in siRNAs without any phosphorothioate stabilization in the sense strand and clearly improved the duration of action in vivo.
Synthesis and biological evaluation of analogs of altohyrtin C (spongistatin 2)
Wagner, Carl E.,Wang, Qiang,Melamed, Alexander,Fairchild, Craig R.,Wild, Robert,Heathcock, Clayton H.
, p. 124 - 136 (2008)
Several structural analogs that contain only part of the altohyrtin structure have been prepared and compared with synthetic altohyrtin C (2) for in vitro cytotoxicity against human colon (HCT116) and ovarian (A2780) cell lines. Whereas altohyrtin C was f
4,4,16-Trifluoropalmitate: Design, Synthesis, Tritiation, Radiofluorination and Preclinical PET Imaging Studies on Myocardial Fatty Acid Oxidation
Colombano, Alessandro,Dall'Angelo, Sergio,Kingston, Lee,Gr?nberg, Gunnar,Correia, Claudia,Passannante, Rossana,Baz, Zuri?e,Morcillo, Miguel ángel,Elmore, Charles S.,Llop, Jordi,Zanda, Matteo
, p. 2317 - 2331 (2020)
Fatty acid oxidation (FAO) produces most of the ATP used to sustain the cardiac contractile work, although glycolysis is a secondary source of ATP under normal physiological conditions. FAO impairment has been reported in the advanced stages of heart failure (HF) and is strongly linked to disease progression and severity. Thus, from a clinical perspective, FAO dysregulation provides prognostic value for HF progression, the assessment of which could be used to improve patient monitoring and the effectiveness of therapy. Positron emission tomography (PET) imaging represents a powerful tool for the assessment and quantification of metabolic pathways in vivo. Several FAO PET tracers have been reported in the literature, but none of them is in routine clinical use yet. Metabolically trapped tracers are particularly interesting because they undergo FAO to generate a radioactive metabolite that is subsequently trapped in the mitochondria, thus providing a quantitative means of measuring FAO in vivo. Herein, we describe the design, synthesis, tritium labelling and radiofluorination of 4,4,16-trifluoro-palmitate (1) as a novel potential metabolically trapped FAO tracer. Preliminary PET-CT studies on [18F]1 in rats showed rapid blood clearance, good metabolic stability – confirmed by using [3H]1 in vitro – and resistance towards defluorination. However, cardiac uptake in rats was modest (0.24±0.04 % ID/g), and kinetic analysis showed reversible uptake, thus indicating that [18F]1 is not irreversibly trapped.
OLIGONUCLEOTIDES CONTAINING NUCLEOTIDE ANALOGS
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Page/Page column 219, (2021/03/13)
The present disclosure relates to double-stranded oligonucleotides, including double-stranded oligonucleotides such as siRNAs, comprising a sense strand oligonucleotide and an antisense strand oligonucleotide, and wherein the antisense strand oligonucleotide comprises one or more nucleotide analogs of formula (I-A) which are neither the 5'-overhang nucleotide nor the 3'-overhang nucleotide of the said antisense strand oligonucleotide, and wherein a nucleotide analog of formula (I-A) is as described in the disclosure. Oligonucleotides containing these analogs have superior biological activity, for example, increased in vitro stability and improved in vivo potency especially improved off-target profiles. The improved oligonucleotides are useful for silencing (e.g., reducing or eradicating) the expression of a target gene.
