Symmetric and dissymmetric carbohydrate-phenyl ditriazole derivatives as DNA G-quadruplex ligands: Synthesis, biophysical studies and antiproliferative activity.,Bioorganic Chemistry

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Symmetric and dissymmetric carbohydrate-phenyl ditriazole derivatives as DNA G-quadruplex ligands: Synthesis, biophysical studies and antiproliferative activity.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-03-21 , DOI: 10.1016/j.bioorg.2020.103786
Matilde Arévalo-Ruiz ₁ , Samir Amrane ₂ , Frédéric Rosu ₃ , Efres Belmonte-Reche ₁ , Pablo Peñalver ₁ , Jean-Louis Mergny ₄ , Juan Carlos Morales ₁

Affiliation

Here we present a novel G4-binding family of compounds based on a central core of phenyl ditriazole (PDTZ) modified with carbohydrates and phenyl pyrrolidinyl side-chains. Their synthesis was achieved using controlled click chemistry conditions to obtain both, symmetric and dissymmetric carb-PDTZ derivatives without any intermediate protecting steps through an optimized methodology. Binding of the new carb-PDTZ to a variety of G-quadruplex motifs was examined using different biophysical techniques. The symmetric carb-PDTZ derivatives were not able to stabilize G4, but the dissymmetric ones (containing one sugar and one phenyl pyrrolidinyl side-chain) did. Interestingly, the dissymmetric carb-PDTZ derivatives showed much higher G4 vs duplex DNA selectivity than the control compound PDTZ 1, which contains two phenyl pyrrodilinyl side-chains and no carbohydrates. Their potential antitumoral activity was also investigated by in vitro cytotoxicity measurements on different cancerous cell lines. All carb-PDTZ derivatives showed higher IC50 values than the control PDTZ 1, probably due to the lack of compound stability of some derivatives and to lower cellular uptake.

中文翻译：

对称和不对称的碳水化合物-苯基二三唑衍生物，作为DNA G-四链体配体：合成，生物物理研究和抗增殖活性。

在这里，我们介绍了一种基于碳水化合物和苯基吡咯烷基侧链修饰的苯基二三唑（PDTZ）中心核的化合物的新型G4结合家族。通过控制点击化学条件获得它们的合成，可以通过优化的方法获得对称和不对称的carb-PDTZ衍生物，而无需任何中间保护步骤。使用不同的生物物理技术检查了新的carb-PDTZ与各种G-四链体基序的结合。对称的carb-PDTZ衍生物不能稳定G4，但不对称的衍生物（含有一个糖和一个苯基吡咯烷基侧链）则可以稳定G4。有趣的是，不对称carb-PDTZ衍生物相对于双链DNA选择性显示出比对照化合物PDTZ 1高得多的G4选择性，它包含两个苯基吡咯二亚烷基侧链，不含碳水化合物。还通过对不同癌细胞系的体外细胞毒性测量研究了它们潜在的抗肿瘤活性。所有的carb-PDTZ衍生物均显示出比对照PDTZ 1高的IC50值，这可能是由于某些衍生物缺乏化合物稳定性以及较低的细胞摄取所致。

更新日期：2020-04-20

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