Design, Synthesis, and Evaluation of New Sugar-Substituted Imidazole Derivatives as Selective c-MYC Transcription Repressors Targeting the Promoter G-Quadruplex.
Design, Synthesis, and Evaluation of New Sugar-Substituted Imidazole Derivatives as Selective c-MYC Transcription Repressors Targeting the Promoter G-Quadruplex.
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DOI：
10.1021/acs.jmedchem.2c00467
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发表时间：
2022-09
影响因子：
7.3
通讯作者：
Mao-lin Li;Jing-Mei Yuan;Haoxuan Yuan;Bi-Han Wu;Shi-Liang Huang;Qing-Jiang Li;Tian-Miao Ou;
中科院分区：
文献类型：
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作者：
Mao-lin Li;Jing-Mei Yuan;Haoxuan Yuan;Bi-Han Wu;Shi-Liang Huang;Qing-Jiang Li;Tian-Miao Ou;
c-MYC是肿瘤发生的关键驱动因素。通过用小分子稳定G-四链体（G4）结构来抑制c-MYC的转录是癌症治疗的潜在策略。在此，我们通过将碳水化合物引入我们先前开发的c-MYC G4配体1，设计并合成了49种新的衍生物。在这些化合物中，与d-葡萄糖1，2-原酸酯偶联的19 a显示出比1更好的c-MYC G4结合、稳定和蛋白质结合破坏能力。我们的进一步评估表明，19 a通过靶向启动子G4阻断c-MYC转录，导致三阴性乳腺癌细胞MDA-MB-231中的c-MYC依赖性癌细胞死亡。此外，19 a显著抑制MDA-MB-231小鼠异种移植模型中的肿瘤生长，伴随c-MYC下调。值得注意的是，与1相比，19 a的安全性显著提高。我们的研究结果表明，19 a可能成为一个有前途的抗癌候选人，这表明，引入碳水化合物，以提高G4靶向和抗肿瘤活性是一个可行的选择。
c-MYC is a key driver of tumorigenesis. Repressing the transcription of c-MYC by stabilizing the G-quadruplex (G4) structure with small molecules is a potential strategy for cancer therapy. Herein, we designed and synthesized 49 new derivatives by introducing carbohydrates to our previously developed c-MYC G4 ligand 1. Among these compounds, 19a coupled with a d-glucose 1,2-orthoester displayed better c-MYC G4 binding, stabilization, and protein binding disruption abilities than 1. Our further evaluation indicated that 19a blocked c-MYC transcription by targeting the promoter G4, leading to c-MYC-dependent cancer cell death in triple-negative breast cancer cell MDA-MB-231. Also, 19a significantly inhibited tumor growth in the MDA-MB-231 mouse xenograft model accompanied by c-MYC downregulation. Notably, the safety of 19a was dramatically improved compared to 1. Our findings indicated that 19a could become a promising anticancer candidate, which suggested that introducing carbohydrates to improve the G4-targeting and antitumor activity is a feasible option.