Design, Synthesis, and Evaluation of Novel p-(Methylthio)styryl Substituted Quindoline Derivatives as Neuroblastoma RAS (NRAS) Repressors via Specific Stabilizing the RNA G-Quadruplex
Design, Synthesis, and Evaluation of Novel p-(Methylthio)styryl Substituted Quindoline Derivatives as Neuroblastoma RAS (NRAS) Repressors via Specific Stabilizing the RNA G-Quadruplex
复制标题
通过特异性稳定 RNA G-四链体作为神经母细胞瘤 RAS (NRAS) 抑制剂的新型对（甲硫基）苯乙烯基取代的喹啉衍生物的设计、合成和评估
DOI：
10.1021/acs.jmedchem.8b00257
复制
发表时间：
2018-08-09
影响因子：
7.3
通讯作者：
Ou, Tian-Miao
中科院分区：
文献类型：
--
作者：
Peng, Wang;Sun, Zhi-Yin;Ou, Tian-Miao
人神经母细胞瘤RAS(NRAS)基因在其5‘端非翻译区(5’-UTR)含有一个富含鸟嘌呤的序列，可形成RNAG-四链结构。这种结构作为NRAS翻译的抑制子，可能成为抗癌药物的潜在靶点。我们以前的研究发现了一种有效的支架--吲哚林支架，用于结合和稳定DNA G-四链结构。本论文在前人研究的基础上，结合已报道的RNA特异性探针，设计、合成了一系列新型的对甲硫基苯乙烯基取代喹乙醇(MSQ)类化合物，并将其鉴定为NRAS RNAG-四链配体。多组实验证明，对甲硫基苯乙烯基侧链的引入可以增强与NRAS RNA G-四链的特异性结合。其中，4a-10在G-四链上显示出很强的稳定活性，随后抑制了NRAS的翻译，抑制了肿瘤细胞的增殖。我们的发现为发现新的NRAS抑制子提供了一种新的策略，通过与mRNA 5‘-UTR区中的RNAG-四链特异性结合来发现新的NRAS抑制子。
The human proto-oncogene neuroblastoma RAS (NRAS) contains a guanine-rich sequence in the S'-untranslated regions (5'-UTR) of the mRNA that could form an RNA G-quadruplex structure. This structure acts as a repressor for NRAS translation and could be a potential target for anticancer drugs. Our previous studies found an effective scaffold, the quindoline scaffold, for binding and stabilizing the DNA G-quadruplex structures. Here, on the basis of the previous studies and reported RNA-specific probes, a series of novel p-(methylthio)styryl substituted quindoline (MSQ) derivatives were designed, synthesized, and evaluated as NRAS RNA G-quadruplex ligands. Panels of experiments turned out that the introduction of p-(methylthio)styryl side chain could enhance the specific binding to the NRAS RNA G-quadruplex. One of the hits, 4a-10, showed strong stabilizing activity on the G-quadruplex and subsequently repressed NRAS's translation and inhibited tumor cells proliferation. Our finding provided a novel strategy to discover novel NRAS repressors by specifically binding to the RNA G-quadruplex in the 5'-UTR of mRNA.