SAR-guided development of indole-matrine hybrids as potential anticancer agents via mitochondrial stress/cytochrome c/caspase 3 signaling pathway.

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Lingyu Li, Jingrong Li, Liyan Ma, Hai Shang, Z. Zou
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引用次数: 1

Abstract

Matrine is a clinically used adjuvant anticancer drug, yet its mild potency limited its application. To improve the anticancer activity of matrine, a total of 31 indole-matrine hybrids were constructed in four rounds of SAR-guided iterative structural optimization process. All of the synthesized compounds were evaluated for their antiproliferative activities against a panel of four human cancer cell lines (Hela, MCF-7, SGC-7901, HepG2) and two normal cell lines (GES-1, LO2). The most active hybrid 8g exhibited the anticancer IC50 values of 0.9 to 1.2 μM, which was 3-magnitude of orders more potent than matrine. 8g also showed better selectivity towards cancer cells with the selectivity index value raised from 1.5 to 6.2. Mechanistic studies demonstrated a mitochondrial distribution for 8g by intracellular click chemistry approaches, which led to the discovery that 8g strongly induced mitochondrial stress, as evidenced by impaired energy metabolism, depolarized mitochondrial membrane potential, overload of mitochondrial calcium and escalated ROS production. 8g-induced mitochondrial stress further led to the release of cytochrome c and subsequent activation of caspase 3, which significantly promoted cellular death and inhibited colony formation.
sar引导下通过线粒体应激/细胞色素c/caspase 3信号通路开发吲哚-苦参碱杂种作为潜在的抗癌药物。
苦参碱是临床上常用的辅助抗癌药物,但其效力弱,限制了其应用。为了提高苦参碱的抗癌活性,通过4轮sar引导迭代结构优化,构建了31个吲哚-苦参碱杂合体。所有合成的化合物对四种人类癌细胞系(Hela, MCF-7, SGC-7901, HepG2)和两种正常细胞系(GES-1, LO2)的抗增殖活性进行了评估。活性最强的杂种8g的抗癌IC50值为0.9 ~ 1.2 μM,比苦参碱强3个数量级。8g对癌细胞的选择性也较好,选择性指数由1.5提高到6.2。机制研究通过细胞内点击化学方法证实了8g的线粒体分布,从而发现8g强烈诱导线粒体应激,表现为能量代谢受损、线粒体膜电位去极化、线粒体钙超载和ROS生成增加。8g诱导的线粒体应激进一步导致细胞色素c的释放和随后的caspase 3的激活,从而显著促进细胞死亡,抑制集落形成。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Bioorganic Chemistry
Bioorganic Chemistry 生物-生化与分子生物学
CiteScore
9.70
自引率
3.90%
发文量
679
审稿时长
31 days
期刊介绍: Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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