Synthesis and physical and biological properties of 1,3-diaza-2-oxophenoxazine-conjugated oligonucleotides

Yamaji, Ryohei; Nakagawa, Osamu; Kishimoto, Yuki; Fujii, Akane; Matsumura, Tomoki; Nakayama, Taisuke; Kamada, Haruhiko; Osawa, Takashi; Yamaguchi, Takao; Obika, Satoshi

doi:10.1016/j.bmc.2022.116972

Cited by 5 publications

(4 citation statements)

References 58 publications

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“… 26 Moreover, several papers showed that ligands against the sigma-1 receptor exhibit a characteristic structural pattern as aminoalkyl group attached to a hydrophobic aromatic ring and the G-clamp modification poses a similar structure to the groups. 27 , 28 , 29 We then hypothesized that the G-clamp modifications in the ASOs have a capability to interact with the sigma-1 receptor and modulate calcium levels in neurons, leading to the improvements of the neurotoxicity in mice injected with the ASOs.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, G-clamp structurally resembles sigma-1 receptor agonists. 27 , 28 , 29 In vitro studies have shown that sigma-1 receptors are rapidly upregulated under cellular stress and play a role in regulating intracellular calcium homeostasis. 24 , 25 Agonists of the sigma-1 receptor have been shown to potentiate increases in intracellular free calcium levels associated with the activation of inositol 1,4,5-trisphosphate receptors, while antagonists reduce this calcium signal.…”

Section: Discussionmentioning

confidence: 99%

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Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2′,4′-BNA/LNA with 9-(aminoethoxy)phenoxazine

Matsubayashi,

Yoshioka,

Lei Mon

et al. 2024

Molecular Therapy - Nucleic Acids

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2′,4′-BNA/LNA with 9-(aminoethoxy)phenoxazine

Matsubayashi,

Yoshioka,

Lei Mon

et al. 2024

Molecular Therapy - Nucleic Acids

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“…ASOs can achieve precise targeting by inducing mRNA degradation, blocking transcription, and interfering with regulatory molecules. [ 125 ] Moreover, the efficiency, stability, and specificity of delivery in vivo are crucial issues that require further development. In the future, artificial intelligence and big data analysis can be used to analyze large‐scale biological information and provide novel insights into the prediction and optimization of therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

The Expanding Roles of Long Non‐Coding RNAs in Pancreatic Cancer

Yan,

Wu,

Yang

et al. 2023

Advanced Therapeutics

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Pancreatic cancer is a clinically challenging disease with a poor survival rate and is one of the leading causes of cancer‐related morbidity. It is highly resistant to treatment and effective diagnostic tools during the early stages of the disease are lacking. Long non‐coding RNAs (lncRNAs) participate extensively in the physiological processes of various diseases, especially multiple types of cancers. lncRNAs have been shown to perform essential functions and are gaining increasing attention in pancreatic cancer research. This review summarizes the roles of lncRNAs in the occurrence, development, and therapeutic resistance of pancreatic cancer by categorizing their regulation of epigenetic inheritance, transcription, post‐transcription, and related signaling pathways. Potential clinical implications, including diagnostic and prognostic biomarkers, as well as the therapeutic prospects of these lncRNAs in pancreatic cancer, are also discussed. Novel insights into the role of lncRNAs in the pathogenesis of pancreatic cancer may help researchers develop novel therapeutic strategies.This article is protected by copyright. All rights reserved

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“…It can form four hydrogen bonds with guanine and increases DNA duplex stability [9][10][11], thus enhancing the affinity and selectivity of target DNA binding [12]. G-clamp-containing oligonucleotides are actively improving [13,14] and quite useful for various biomedical and research applications [15][16][17][18][19][20]. The oxoG-clamp has emerged as an extension of the G-clamp idea [21].…”

Section: Introductionmentioning

confidence: 99%

Structural and Dynamic Features of the Recognition of 8-oxoguanosine Paired with an 8-oxoG-clamp by Human 8-oxoguanine-DNA Glycosylase

Lukina,

Zhdanova,

Koval

2024

CIMB

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8-oxoguanine (oxoG) is formed in DNA by the action of reactive oxygen species. As a highly mutagenic and the most common oxidative DNA lesion, it is an important marker of oxidative stress. Human 8-oxoguanine-DNA glycosylase (OGG1) is responsible for its prompt removal in human cells. OGG1 is a bifunctional DNA glycosylase with N-glycosylase and AP lyase activities. Aspects of the detailed mechanism underlying the recognition of 8-oxoguanine among numerous intact bases and its subsequent interaction with the enzyme’s active site amino acid residues are still debated. The main objective of our work was to determine the effect (structural and thermodynamic) of introducing an oxoG-clamp in model DNA substrates on the process of 8-oxoG excision by OGG1. Towards that end, we used DNA duplexes modeling OGG1-specific lesions: 8-oxoguanine or an apurinic/apyrimidinic site with either cytidine or the oxoG-clamp in the complementary strand opposite to the lesion. It was revealed that there was neither hydrolysis of the N-glycosidic bond at oxoG nor cleavage of the sugar–phosphate backbone during the reaction between OGG1 and oxoG-clamp-containing duplexes. Possible structural reasons for the absence of OGG1 enzymatic activity were studied via the stopped-flow kinetic approach and molecular dynamics simulations. The base opposite the damage was found to have a critical effect on the formation of the enzyme–substrate complex and the initiation of DNA cleavage. The oxoG-clamp residue prevented the eversion of the oxoG base into the OGG1 active site pocket and impeded the correct convergence of the apurinic/apyrimidinic site of DNA and the attacking nucleophilic group of the enzyme. An obtained three-dimensional model of the OGG1 complex with DNA containing the oxoG-clamp, together with kinetic data, allowed us to clarify the role of the contact of amino acid residues with DNA in the formation of (and rearrangements in) the enzyme–substrate complex.

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Synthesis and physical and biological properties of 1,3-diaza-2-oxophenoxazine-conjugated oligonucleotides

Cited by 5 publications

References 58 publications

Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2′,4′-BNA/LNA with 9-(aminoethoxy)phenoxazine

Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2′,4′-BNA/LNA with 9-(aminoethoxy)phenoxazine

The Expanding Roles of Long Non‐Coding RNAs in Pancreatic Cancer

Structural and Dynamic Features of the Recognition of 8-oxoguanosine Paired with an 8-oxoG-clamp by Human 8-oxoguanine-DNA Glycosylase

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