Syntheses and evaluation of acridone derivatives as anticancer agents targeting Kras promoter i-motif structure.
Syntheses and evaluation of acridone derivatives as anticancer agents targeting Kras promoter i-motif structure.
复制标题
DOI：
10.1016/j.bioorg.2023.106526
复制
发表时间：
2023-04
影响因子：
5.1
通讯作者：
Zuzhuang Wei;Xiaomin Lin;Siyi Wang;Jiahui Zhang;Dongsheng Ji;Xue Gong;Zhishu Huang;B. Shu;Ding Li
中科院分区：
文献类型：
--
作者：
Zuzhuang Wei;Xiaomin Lin;Siyi Wang;Jiahui Zhang;Dongsheng Ji;Xue Gong;Zhishu Huang;B. Shu;Ding Li
设计合成了两个系列的吖啶酮类化合物，并对其抗癌活性进行了评价。这些化合物中的大多数对癌细胞系显示出有效的抗增殖活性。其中，具有双1，2，3-三唑基团的化合物C4显示出最强的抗Hep-G2细胞活性，IC 50值测定为6.29 ± 0.93 μM。随后的实验表明，C4能与Kras基因启动子i-motif结构结合并破坏其稳定性，但与相应的G-quadruplex没有明显的相互作用，C4能下调Hep-G2细胞中Kras的表达，可能与其与Kras i-motif的相互作用有关。进一步的细胞学研究表明C4可诱导Hep-G2细胞凋亡，其机制可能与影响线粒体功能有关。这些结果表明，C4可作为一种有前途的抗癌药物进一步开发。
Two series of novel acridone derivatives were designed and synthesized, with their anticancer activity evaluated. Most of these compounds showed potent antiproliferative activity against cancer cell lines. Among them, compoundC4with dual 1,2,3-triazol moieties exhibited the most potent activity against Hep-G2 cells with IC50value determined to be 6.29 ± 0.93 μM. Subsequent experiments showed thatC4could bind to and destabilize Kras gene promoter i-motif structure without significant interaction with its corresponding G-quadruplex.C4could down-regulate Kras expression in Hep-G2 cells, possibly due to its interaction with the Kras i-motif. Further cellular studies indicated thatC4could induce apoptosis of Hep-G2 cells, possibly related to its effect on mitochondrial dysfunction. These results indicated thatC4could be further developed as a promising anticancer agent.