Syntheses and Evaluation of New Bisacridine Derivatives for Dual Binding of G-Quadruplex and i-Motif in Regulating Oncogene c-myc Expression
Syntheses and Evaluation of New Bisacridine Derivatives for Dual Binding of G-Quadruplex and i-Motif in Regulating Oncogene c-myc Expression
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DOI：
10.1021/acs.jmedchem.9b01917
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发表时间：
2020-09-10
影响因子：
7.3
通讯作者：
Li，Ding
中科院分区：
文献类型：
--
作者：
Kuang，Guotao;Zhang，Meiling;Li，Ding
大肠杆菌癌基因是细胞生长和分化的重要调控因子，其异常过表达与多种肿瘤的发生发展密切相关。因此，已经研究了c-myc转录和表达的抑制用于癌症治疗。本研究合成了多种新的双吖啶衍生物，并评价了它们与c-myc启动子G-四链体和i-基序的结合。结果表明，a9能与G-quadruplex和i-motif结合，稳定c-mycgene的转录，抑制癌细胞增殖，诱导SiHa细胞凋亡和周期阻滞; a9在SiHa异种移植瘤模型中表现出肿瘤生长抑制活性，这可能与其与c-mycgene启动子G-quadruplex和i-motif结合有关。我们的研究结果表明，α 9作为一个双重G-四链体/i-基序结合剂可以有效地在癌基因的复制和转录，并成为一个有前途的先导化合物，为进一步开发与改善的效力和选择性。
Thec-myconcogene is an important regulator for cell growth and differentiation, and its aberrant overexpression is closely related to the occurrence and development of various cancers. Thus, the suppression ofc-myctranscription and expression has been investigated for cancer treatment. In this study, various new bisacridine derivatives were synthesized and evaluated for their binding withc-mycpromoter G-quadruplex and i-motif. We found thata9could bind to and stabilize both G-quadruplex and i-motif, resulting in the downregulation ofc-mycgene transcription.a9could inhibit cancer cell proliferation and induce SiHa cell apoptosis and cycle arrest.a9exhibited tumor growth inhibition activity in a SiHa xenograft tumor model, which might be related to its binding withc-mycpromoter G-quadruplex and i-motif. Our results suggested thata9as a dual G-quadruplex/i-motif binder could be effective in both oncogene replication and transcription and become a promising lead compound for further development with improved potency and selectivity.