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

Abstract

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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“…7) strengthens the evidence for C3 -induced cell death through the apoptosis pathway. 70–74 The observed decrease in BCL-2 expression, in conjunction with the increased ROS levels and release of cytochrome C, further supports the involvement of mitochondria in the apoptotic process induced by C3 treatment.…”

Synthesis, Anti‐adipogenic, and Insulin‐sensitizing Potential of Benzosuberene‐alkyl Sulfone (BSAS) Analogues

“…Cellular apoptosis was performed using an ApoDETECT Annexin V-FITC kit (Life Technologies, California, USA) as per the previously mentioned protocol. [47] Briefly, cells were differentiated into myotubes and treated with 25 μM BSAS-(1-5) analogues for 24 h before being exposed to H 2 O 2 . Cells were centrifuged at 2000 rpm for 5 minutes.…”