Structure modification and biological evaluation of indole-chalcone derivatives as anti-tumor agents through dual targeting tubulin and TrxR

Yan, Jun; Xu, Yuzhu; Jin, Xing; Zhang, Qiaoxuan; Ouyang, Feng; Han, Liqiao; Zhan, Min; Li, Xingshu; Liang, Biao; Huang, Xianzhang

doi:10.1016/j.ejmech.2021.113897

Cited by 20 publications

(14 citation statements)

References 33 publications

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“…Additionally, we also observed the elevated levels of ROS in HNSCC cells treated with 3-methyleneisoindolinone, which is characterized by an increased DFC content (green fluorescence) after treatment of 50 μM of compounds for 4 h (Figure ). Results clearly indicate that the isoindolinone derivatives have generated intracellular oxidative stress and disrupted the mitochondrial membrane potential (ΔΨm) in the HNSCC cells similar to the potent anticancer compounds in recent studies. , Therefore, it could be characterized as the potential of 3-methyleneisoindolinones to work as potent anticancer agents. However, in order to accentuate the results and delve deeper into the mode of action of the compounds, the effects of the 3-methyleneisoindolinones on key cellular processes like cell cycle and apoptosis were evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…This indicates the ability of 3-methyleneisoindolinone to disturb the cell cycle process, which was in consonance with previous findings of a similar category of anticancer compounds. 31 , 35 , 36 However, it was interesting to find that all the three leads arrest the cell cycle in different phases and could have a different mode of action on cancer cells. Additionally, a dose-dependent increase in the percentage of the cell population was observed in the Sub-G1 phase for 3n and 3h , indicating the presence of cellular apoptosis ( Figure 7 c,e).…”

Section: Resultsmentioning

confidence: 99%

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Novel 3-Methyleneisoindolinones Diversified via Intramolecular Heck Cyclization Induce Oxidative Stress, Decrease Mitochondrial Membrane Potential, Disrupt Cell Cycle, and Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells

et al. 2022

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer in the world and the most prevalent cancer of developing countries. Increased disease burden and a smaller number of approved targeted therapies are a growing concern worldwide. Isoindolinone motifs have been a central part of many pharmacological compounds, and their derivatives possess substantial anticancer potential. However, their anticancer potential against HNSCC has not been well investigated. In the current study, a series of 3-methyleneisoindolinones have been designed and synthesized and their late-stage intramolecular Heck cyclization was achieved to evaluate their anticancer potential against HNSCC cells. Additionally, in silico ADME profiling of synthesized compounds revealed their drug-likeness properties as potential drug candidates. Among the synthesized compounds, 3-bromo-5-methylpyridin-2-yl-3-methyleneisoindolin-1-one, i.e., 3n, with a pyridyl unit exhibited the most significant cytotoxicity against HNSCC cells. The cytotoxic potential of synthesized compounds varied depending on the nature of substituents present and has been well established with structure–activity relationship studies. Further, flow cytometric analysis showed that 3f, 3h, and 3n triggered intracellular oxidative stress, disrupted mitochondrial membrane potential, and interrupted the cell cycle of HNSCC cells in the S-phase and sub-G1 phase. Further, 3f, 3h, and 3n also exhibited pro-apoptotic potential and induced cellular apoptosis in the HNSCC cells. Overall, the findings of this study attributed 3-methyleneisoindolinone chemistry and efficacy evaluation and corroborated their anticancer potential against HNSCC. It will pave the way to further design and optimize novel 3-methyleneisoindolinone as effective antitumor agents, which may provide effective treatment modalities against HNSCC.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Novel 3-Methyleneisoindolinones Diversified via Intramolecular Heck Cyclization Induce Oxidative Stress, Decrease Mitochondrial Membrane Potential, Disrupt Cell Cycle, and Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells

et al. 2022

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“…The activity of compound 178 is correlated with its ability to bind to the binding site of β-tubulin colchicine [ 227 ]. Other indole-chalcone derivatives were analyzed from the point of view of anti-tumor activity, related to tubulin and TrxR [ 228 ].…”

Section: Flavonoidsmentioning

confidence: 99%

Two Important Anticancer Mechanisms of Natural and Synthetic Chalcones

Constantinescu

Mihis

2022

IJMS

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ATP-binding cassette subfamily G and tubulin pharmacological mechanisms decrease the effectiveness of anticancer drugs by modulating drug absorption and by creating tubulin assembly through polymerization. A series of natural and synthetic chalcones have been reported to have very good anticancer activity, with a half-maximal inhibitory concentration lower than 1 µM. By modulation, it is observed in case of the first mechanism that methoxy substituents on the aromatic cycle of acetophenone residue and substitution of phenyl nucleus by a heterocycle and by methoxy or hydroxyl groups have a positive impact. To inhibit tubulin, compounds bind to colchicine binding site. Presence of methoxy groups, amino groups or heterocyclic substituents increase activity.

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“…Meanwhile, acrolein moiety was also extensively used as a highly active linker in the design of antitumor agents. Yan’s group designed and synthesized a series of chalcone derivatives via the combination of indole and 3,4-dimethoxy-5-(methylselanyl)phenyl group by acrolein linker, among which the newly obtained compound J ( Figure 1J ) served as a dual-targeting inhibitor of tubulin and thioredoxin reductases, exhibiting superior anti-proliferative activities towards various human cancer cells with IC 50 values of 8–35 nM ( Yan et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and anticancer activity studies of 3-(coumarin-3-yl)-acrolein derivatives: Evidenced by integrating network pharmacology and vitro assay

Chen

Cai

et al. 2023

Front. Pharmacol.

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Coumarin derivatives have diverse structures and show various significant biological activities. Aiming to develop more potent coumarin derivatives for cancer treatment, a series of coumarin acrolein hybrids were designed and synthesized by using molecular hybridization approach, and investigated for their antiproliferative activity against A549, KB, Hela and MCF-7 cancer cells as well as HUVEC and LO2 human normal cells. The results indicated that most of the synthesized compounds displayed remarkable inhibitory activity towards cancer cells but low cytotoxicity on normal cells. Among all the compounds, 5d and 6e were the most promising compounds against different cancer cell lines, especially for A549 and KB cells. The preliminary action mechanism studies suggested that compound 6e, the representative compound, was capable of dose-dependently suppressing migration, invasion and inducing significant apoptosis. Furthermore, the combined results of network pharmacology and validation experiments revealed that compound 6e induced mitochondria dependent apoptosis via the PI3K/AKT-mediated Bcl-2 signaling pathway. In summary, our study indicated compound 6e could inhibit cell proliferation, migration, invasion and promote cell apoptosis through inhibition of PI3K/AKT signaling pathway in human oral epidermoid carcinoma cells. These findings demonstrated the potential of 3-(coumarin-3-yl)-acrolein derivatives as novel anticancer chemotherapeutic candidates, providing ideas for further development of drugs for clinical use.

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Structure modification and biological evaluation of indole-chalcone derivatives as anti-tumor agents through dual targeting tubulin and TrxR

Cited by 20 publications

References 33 publications

Novel 3-Methyleneisoindolinones Diversified via Intramolecular Heck Cyclization Induce Oxidative Stress, Decrease Mitochondrial Membrane Potential, Disrupt Cell Cycle, and Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells

Novel 3-Methyleneisoindolinones Diversified via Intramolecular Heck Cyclization Induce Oxidative Stress, Decrease Mitochondrial Membrane Potential, Disrupt Cell Cycle, and Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells

Two Important Anticancer Mechanisms of Natural and Synthetic Chalcones

Design, synthesis and anticancer activity studies of 3-(coumarin-3-yl)-acrolein derivatives: Evidenced by integrating network pharmacology and vitro assay

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