Synthesis, cytotoxicity, oxidative stress, anti-metastatic and anti-inflammatory effects of novel 2-methylene-1H-indene-1,3-dione tethered 2-(2-methoxyphenoxy)-N-arylacetamide: induction of apoptosis in HCT116 and HeLa cells

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions Pub Date : 2025-05-10 DOI:10.1016/j.cbi.2025.111549

Nada S. Ibrahim , Eman Hatem Shoukry , Marwa Sharaky , Hadeer M. Diab , Ahmed H.M. Elwahy , Ismail A. Abdelhamid

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引用次数: 0

Abstract

Six novel chalcones were synthesized, and their structures were confirmed using various spectral tools. All the prepared compounds were subjected to SRB cytotoxic screening against nine cancer and two normal cell lines. Compound 7a showed the highest impact against colorectal carcinoma (HCT116) and cervical cancer (HeLa) with IC₅₀ values of 4.6 ± 0.03 and 5.5 ± 0.1 μg/mL, respectively, compared to doxorubicin (4.8 ± 0.4 and 5.7 ± 0.4 μg/mL, respectively). ELISA assay revealed that the apoptotic proteins (P53, Bax, caspases-3, -8, and -9) and the oxidative marker (Malondialdehyde (MDA)) were significantly activated in 7a treated HCT116 and HeLa cells. However, the anti-metastatic markers (Matrix metalloproteinase 2 (MMP2) and Matrix metalloproteinase-9 (MMP9)), anti-apoptotic Bcl2, antioxidant Glutathione (GSH), and anti-inflammatory (interleukin (IL)-6, and IL-1β) were inhibited in HCT116 and HeLa cells treated with 7a. Flow-cytometric analysis of the cell cycle revealed that the percentage of cells in S and G2/M phases in 7a treated HCT116 cells was increased. After 24 h of treatment, Hela-treated cells had a slightly higher proportion of G0/G1 cells. Comet assay demonstrated that compound 7a caused DNA damage with a percentage of 26.22 ± 1.1 % in HCT116 compared to the untreated cells (6.18 ± 0.88 %). Theoretical molecular modeling against P53 cancer mutant Y220C and Bcl2 showed binding energies of −22.7 and −23.3 kcal/mol, respectively, which confirmed our ELISA results.

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新型2-亚甲基- 1h -茚-1,3-二酮系2-（2-甲氧基苯氧基）- n -芳基乙酰胺的合成、细胞毒性、氧化应激、抗转移和抗炎作用：诱导HCT116和HeLa细胞凋亡

合成了6种新型查尔酮，并利用各种光谱工具对其结构进行了确证。制备的化合物对9种肿瘤和2种正常细胞系进行了SRB细胞毒筛选。化合物7a对结直肠癌（HCT116）和宫颈癌（HeLa）的IC50值分别为4.6±0.03和5.5±0.1 μg/mL，高于阿霉素（4.8±0.4和5.7±0.4 μg/mL）。ELISA检测显示，7a处理的HCT116和HeLa细胞中凋亡蛋白（P53、Bax、caspase -3、-8和-9）和氧化标志物（丙二醛（MDA））显著活化。然而，抗转移标志物（基质金属蛋白酶2 （MMP2）和基质金属蛋白酶9 (MMP9)）、抗凋亡Bcl2、抗氧化谷胱甘肽（GSH）和抗炎（白细胞介素(IL)-6和IL-1β）在7a处理的HCT116和HeLa细胞中均被抑制。流式细胞术细胞周期分析显示，7a处理的HCT116细胞处于S期和G2/M期的细胞比例增加。处理24 h后，hela处理的细胞中G0/G1细胞比例略高。彗星试验表明，化合物7a对HCT116细胞的DNA损伤率为26.22±1.1%，而未处理细胞的损伤率为6.18±0.88%。P53突变体Y220C和Bcl2的理论分子模型显示结合能分别为- 22.7和- 23.3 kcal/mol，与我们的ELISA结果一致。

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来源期刊

Chemico-Biological Interactions 生物-毒理学

CiteScore

7.70

自引率

3.90%

发文量

410

审稿时长

36 days

期刊介绍： Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.