New Disubstituted Quindoline Derivatives Inhibiting Burkitt’s Lymphoma Cell Proliferation by Impeding c-MYC Transcription,Journal of Medicinal Chemistry

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New Disubstituted Quindoline Derivatives Inhibiting Burkitt’s Lymphoma Cell Proliferation by Impeding c-MYC Transcription
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-06-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00099
Hui-Yun Liu ₁ , Ai-Chun Chen ₁ , Qi-Kun Yin ₁ , Zeng Li ₁ , Su-Mei Huang ₁ , Gang Du ₁ , Jin-Hui He ₁ , Li-Peng Zan ₁ , Shi-Ke Wang ₁ , Yao-Hao Xu ₁ , Jia-Heng Tan ₁ , Tian-Miao Ou ₁ , Ding Li ₁ , Lian-Quan Gu ₁ , Zhi-Shu Huang ₁

Affiliation

The c-MYC oncogene is overactivated during Burkitt’s lymphoma pathogenesis. Targeting c-MYC to inhibit its transcriptional activity has emerged as an effective anticancer strategy. We synthesized four series of disubstituted quindoline derivatives by introducing the second cationic amino side chain and 5-N-methyl group based on a previous study of SYUIQ-5 (1) as c-MYC promoter G-quadruplex ligands. The in vitro evaluations showed that all new compounds exhibited higher stabilities and binding affinities, and most of them had better selectivity (over duplex DNA) for the c-MYC G-quadruplex compared to 1. Moreover, the new ligands prevented NM23-H2, a transcription factor, from effectively binding to the c-MYC G-quadruplex. Further studies showed that the selected ligand, 7a4, down-regulated c-MYC transcription by targeting promoter G-quadruplex and disrupting the NM23-H2/c-MYC interaction in RAJI cells. 7a4 could inhibit Burkitt’s lymphoma cell proliferation through cell cycle arrest and apoptosis and suppress tumor growth in a human Burkitt’s lymphoma xenograft.

中文翻译：

通过阻止c-MYC转录抑制伯基特淋巴瘤细胞增殖的新的二取代的喹喔啉衍生物

在伯基特氏淋巴瘤的发病机理中，c-MYC癌基因被过度激活。靶向c-MYC抑制其转录活性已成为一种有效的抗癌策略。我们基于SYUIQ-5（1）作为c-MYC启动子G-四链体配体的先前研究，通过引入第二个阳离子氨基侧链和5- N-甲基合成了四个系列的双取代喹啉衍生物。在体外评价表明，所有的新化合物表现出更高的稳定性和结合亲和力，和其中大部分具有用于更好的选择性（超过双链体DNA）的c-MYC相比G-四链体1。此外，新的配体阻止了转录因子NM23-H2有效地与c-MYC G-四链体结合。进一步的研究表明，选定的配体7a4通过靶向启动子G-四链体并破坏RAJI细胞中的NM23-H2 / c-MYC相互作用而下调c-MYC转录。7a4可以通过细胞周期停滞和凋亡抑制Burkitt淋巴瘤细胞增殖，并抑制人类Burkitt淋巴瘤异种移植物中的肿瘤生长。

更新日期：2017-06-29

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