| 1529769-00-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• CAS: 1529769-00-3
• 化学式: C₁₇H₂₀N₄O
• 分子量: 296.372
• InChiKey: UXRXYKRYYGTKBD-UHFFFAOYSA-N

反应信息

• 作为反应物：
  描述：

  、 在 copper(l) iodide 、 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 以79%的产率得到
  参考文献：
  名称：

  Targeting the Production of Oncogenic MicroRNAs with Multimodal Synthetic Small Molecules

  摘要：

  MicroRNAs (miRNAs) are a recently discovered category of small RNA molecules that regulate gene expression at the post-transcriptional level. Accumulating evidence indicates that miRNAs are aberrantly expressed in a variety of human cancers and revealed to be oncogenic and to play a pivotal role in initiation and progression of these pathologies. It is now clear that the inhibition of oncogenic miRNAs, defined as blocking their biosynthesis or their function, could find an application in the therapy of different types of cancer in which these miRNAs are implicated. Here we report the design, synthesis, and biological evaluation of new small-molecule RNA ligands targeting the production of oncogenic microRNAs. In this work we focused our attention on miR-372 and miR-373 that are implicated in the tumorigenesis of different types of cancer such as gastric cancer. These two oncogenic miRNAs are overexpressed in gastric cancer cells starting from their precursors pre-miR-372 and pre-miR-373, two stem-loop structured RNAs that lead to mature miRNAs after cleavage by the enzyme Dicer. The small molecules described herein consist of the conjugation of two RNA binding motives, i.e., the aminoglycoside neomycin and different natural and artificial nucleobases, in order to obtain RNA ligands with increased affinity and selectivity compared to that of parent compounds. After the synthesis of this new series of RNA ligands, we demonstrated that they are able to inhibit the production of the oncogenic miRNA-372 and -373 by binding their pre-miRNAs and inhibiting the processing by Dicer. Moreover, we proved that some of these compounds bear anti-proliferative activity toward gastric cancer cells and that this activity is likely linked to a decrease in the production of targeted miRNAs. To date, only few examples of small molecules targeting oncogenic miRNAs have been reported, and such inhibitors could be extremely useful for the development of new anticancer therapeutic strategies as well as useful biochemical tools for the study of miRNAs' pathways and mechanisms. Furthermore, this is the first time that a design based on current knowledge about RNA targeting is proposed in order to target miRNAs' production with small molecules.

  DOI：

  10.1021/cb400668h

文献信息

• Development of 2-deoxystreptamine–nucleobase conjugates for the inhibition of oncogenic miRNA production
  作者：Thi Phuong Anh Tran、Sylvain Poulet、Mélanie Pernak、Anita Rayar、Stéphane Azoulay、Audrey Di Giorgio、Maria Duca

  DOI：10.1039/d1md00345c

  日期：——

  we developed a new series of RNA ligands for the targeting of oncogenic miRNA biogenesis based on the 2-deoxystreptamine scaffold. The latter is part of the aminoglycoside neomycin and is known to play an essential role in the RNA interaction of this class of RNA binders. 2-deoxystreptamine was thus conjugated to natural and artificial nucleobases to obtain new binders of the oncogenic miR-372 precursor

  发现用于选择性 RNA 靶向的新原始支架是当前药物化学的主要挑战之一，因为治疗相关的 RNA 代表了许多病理学的潜在靶标。最近的努力一直致力于寻找靶向致癌 miRNA 生物发生的 RNA 配体，这些 miRNA 的过度表达与各种癌症的发展直接相关。在这项工作中，我们基于 2-脱氧链霉胺支架开发了一系列新的 RNA 配体，用于靶向致癌 miRNA 生物合成。后者是氨基糖苷类新霉素的一部分，已知在此类 RNA 结合物的 RNA 相互作用中起着重要作用。因此，2-脱氧链霉胺与天然和人工核碱基结合，以获得致癌 miR-372 前体（pre-miR-372）的新结合剂。