Kinetic Target‐Guided Synthesis of Small‐Molecule G‐Quadruplex Stabilizers,ChemistryOpen

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Kinetic Target‐Guided Synthesis of Small‐Molecule G‐Quadruplex Stabilizers
ChemistryOpen ( IF 2.5 ) Pub Date : 2020-12-03 , DOI: 10.1002/open.202000261
Alice Pomeislová _{1,

2} , Lukáš Vrzal _{1,

3} , Jaroslav Kozák ₁ , Juraj Dobiaš ₁ , Martin Hubálek ₁ , Hana Dvořáková ₃ , Paul E Reyes-Gutiérrez ₁ , Filip Teplý ₁ , Václav Veverka _{1,

4}

Affiliation

The formation of a G‐quadruplex motif in the promoter region of the c‐MYC protooncogene prevents its expression. Accordingly, G‐quadruplex stabilization by a suitable ligand may be a viable approach for anticancer therapy. In our study, we used the 4‐(4‐methylpiperazin‐1‐yl)aniline molecule, previously identified as a fragment library screen hit, as a template for the SAR‐guided design of a new small library of clickable fragments and subjected them to click reactions, including kinetic target‐guided synthesis in the presence of a G‐quadruplex forming oligonucleotide Pu24. We tested the clickable fragments and products of click reactions for their G‐quadruplex stabilizing activity and determined their mode of binding to the c‐MYC G‐quadruplex by NMR spectroscopy. The enhanced stabilizing potency of click products in biology assays (FRET, Polymerase extension assay) matched the increased yields of in situ click reactions. In conclusion, we identified the newly synthesized click products of bis‐amino derivatives of 4‐(4‐methylpiperazin‐1‐yl)aniline as potent stabilizers of c‐MYC G‐quadruplex, and their further evolution may lead to the development of an efficient tool for cancer treatment.

中文翻译：

小分子 G-四链体稳定剂的动力学目标引导合成

c-MYC原癌基因启动子区域中 G-四链体基序的形成阻止了其表达。因此，通过合适的配体稳定 G-四链体可能是抗癌治疗的可行方法。在我们的研究中，我们使用了 4-(4-甲基哌嗪-1-基)苯胺分子（之前被确定为片段库屏幕点击）作为 SAR 引导设计的新小型可点击片段库的模板，并对它们进行了测试点击反应，包括在 G-四链体形成寡核苷酸 Pu24 存在下的动力学靶标引导合成。我们测试了可点击片段和点击反应产物的 G-四链体稳定活性，并通过 NMR 光谱确定了它们与c-MYC G-四链体的结合模式。点击产物在生物学测定（FRET，聚合酶延伸测定）中增强的稳定性与原位点击反应产量的增加相匹配。总之，我们确定了新合成的 4-(4-甲基哌嗪-1-基)苯胺双氨基衍生物的点击产物作为c-MYC G-四联体的有效稳定剂，并且它们的进一步进化可能导致开发癌症治疗的有效工具。

更新日期：2020-12-03

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