23377-40-4Relevant articles and documents
Locked Nucleic Acid Gapmers and Conjugates Potently Silence ADAM33, an Asthma-Associated Metalloprotease with Nuclear-Localized mRNA
Pendergraff, Hannah M.,Krishnamurthy, Pranathi Meda,Debacker, Alexandre J.,Moazami, Michael P.,Sharma, Vivek K.,Niitsoo, Liisa,Yu, Yong,Tan, Yen Nee,Haitchi, Hans Michael,Watts, Jonathan K.
, p. 158 - 168 (2017)
Two mechanisms dominate the clinical pipeline for oligonucleotide-based gene silencing, namely, the antisense approach that recruits RNase H to cleave target RNA and the RNAi approach that recruits the RISC complex to cleave target RNA. Multiple chemical designs can be used to elicit each pathway. We compare the silencing of the asthma susceptibility gene ADAM33 in MRC-5 lung fibroblasts using four classes of gene silencing agents, two that use each mechanism: traditional duplex small interfering RNAs (siRNAs), single-stranded small interfering RNAs (ss-siRNAs), locked nucleic acid (LNA) gapmer antisense oligonucleotides (ASOs), and novel hexadecyloxypropyl conjugates of the ASOs. Of these designs, the gapmer ASOs emerged as lead compounds for silencing ADAM33 expression: several gapmer ASOs showed subnanomolar potency when transfected with cationic lipid and low micromolar potency with no toxicity when delivered gymnotically. The preferential susceptibility of ADAM33 mRNA to silencing by RNase H may be related to the high degree of nuclear retention observed for this mRNA. Dynamic light scattering data showed that the hexadecyloxypropyl ASO conjugates self-assemble into clusters. These conjugates showed reduced potency relative to unconjugated ASOs unless the lipophilic tail was conjugated to the ASO using a biocleavable linkage. Finally, based on the lead ASOs from (human) MRC-5 cells, we developed a series of homologous ASOs targeting mouse Adam33 with excellent activity. Our work confirms that ASO-based gene silencing of ADAM33 is a useful tool for asthma research and therapy.
Synthesis and antiproliferative activity of cytidine-5'-alkylphosphonophosphates and structurally related compounds
Brachwitz,Lachmann,Thomas,Bergmann,Berdel,Langen
, p. 77 - 85 (1996)
The chemical synthesis of cytidine-5'-alkyl- and cytidine-5'-alkyl(acyl)deoxyglycerophosphonophosphates is reported. The compounds obtained represent a novel class of cytostatically active agents based on phospholipids, which inhibit the growth of various tumor cell lines in vitro. They are phosphono analogs of the cytidine-5'-diphosphale-diacylglycerol (CDP-DAG) possessing a structurally modified lipid moiety and a phospholipase C-resistant P-C bond. The antiproliferative efficacy of the cytidine-5'-alkylphosphonophosphates strongly depends on the alkyl chain length. The cytidine-5'-hexadecylphosphonophosphate was found to be the most effective compound tested in this study. Its cytostatic effect was distinctly higher than that of the alkyl(acyl)deoxyglycero derivatives and of the corresponding diphosphates. The structures of the new compounds were confirmed by fast atom bombardment mass spectrometry (FAB). The FAB fragmentation pattern is discussed.
ANTIVIRAL COMPOUNDS
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Paragraph 0597, (2021/08/27)
The present disclosure provides compounds for treating a variety of diseases, such as respiratory syncytial virus (RSV), HRV, hMPV, ebola, Zika, West Nile, Dengue, and HCV.
Novel antiviral nucleoside reverse transcriptase inhibitor
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Paragraph 0311; 0314; 0315; 0316, (2019/04/06)
The invention relates to a novel antiviral nucleoside reverse transcriptase inhibitor compound, a pharmaceutical composition comprising the same and preparation and application thereof. Particularly,the invention discloses a condensed pyrimidine compound
