发现新的β-碳碱/褪黑素杂交体作为STAT3抑制剂，通过增加DNA损伤治疗肺癌

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-05-06 DOI:10.1016/j.bmc.2025.118227

Xiaojuan Yang , Shuting Jia , Chao Xia , Yuping Yang

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引用次数: 0

摘要

基于STAT3抑制剂与DNA损伤剂之间存在显著的协同作用，我们设计并合成了一系列β-碳碱/褪黑激素杂交体作为STAT3抑制剂，通过增加DNA损伤。其中，DT10对A549和HepG2细胞表现出较强的体外抗肿瘤能力，IC50值分别为0.44 μM和1.89 μM。机制研究表明，DT10可降低A549细胞中p-STAT3水平，抑制STAT3核易位（IC50 = 2.06±0.55 μM），上调DNA损伤标志物γ-H2AX和53BP1。DT10抑制A549细胞迁移，促进A549细胞凋亡。综上所述，DT10具有较强的抗癌作用，是人类肺癌的候选治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Discovery of novel β-carboline/melatonin hybrids as STAT3 inhibitors for the treatment of lung cancer via increasing DNA damage

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Discovery of novel β-carboline/melatonin hybrids as STAT3 inhibitors for the treatment of lung cancer via increasing DNA damage

Based on the facts that significant synergistic effects exist between STAT3 inhibitors and DNA damage agents, we herein designed and synthesized a series of β-carboline/melatonin hybrids as STAT3 inhibitors via increasing DNA damage. Among them, DT10 exhibited superior in vitro antitumor potency against A549 and HepG2 cells, with IC₅₀ values of 0.44 and 1.89 μM, respectively. Mechanistic investigations revealed that DT10 could reduce p-STAT3 levels, inhibit STAT3 nuclear translocation (IC₅₀ = 2.06 ± 0.55 μM), and upregulate the DNA damage markers γ-H2AX and 53BP1 in A549 cells. Additionally, DT10 suppressed the migration and promoted the apoptosis of A549 cells. Overall, DT10 has a strong anticancer effect and is a candidate therapeutic target for human lung cancer.

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.