article · Scientific Reports
Novel hybrid compounds combining phthalimide and acridine-1,8-dione structures were created using a three-step synthetic process. Laboratory evaluations measured the cytotoxic and antitumour effects of five specific derivatives against four cancer cell lines representing skin, lung, and breast cancers, alongside non-cancerous human skin fibroblast cells. Among these, the compound designated as 8f demonstrated notable activity against lung and skin cancer cells, displaying favourable half-maximal inhibitory concentrations and selectivity indices. Analysis of gene expression in treated skin cancer cells indicated changes in key genes including p53, TOP2B, p38, and EGFR. Furthermore, computational docking models indicated strong binding affinities between compound 8f and these target proteins, pointing to a dual mechanism of action. These findings suggest that 8f represents a lead candidate for continued anticancer drug development.
Finding new cancer therapies that specifically target tumour cells without harming healthy tissue remains a major medical challenge. Developing hybrid chemical molecules that act on multiple cellular targets can improve treatment effectiveness against aggressive cancers such as lung and skin malignancies. This research identifies a specific chemical structure that shows selective toxicity toward cancer cells while altering crucial cancer-related genes.
This work could enable early lead optimisation for pharmaceutical developers seeking targeted small-molecule oncology therapeutics. The primary users would be medicinal chemists and preclinical drug discovery teams working on lung and skin cancer treatments. The research is at an early laboratory stage, limited to chemical synthesis, in vitro cell assays, and computational docking, meaning extensive in vivo efficacy, safety, and pharmacokinetic testing is required before clinical use.
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Abstract In this study, we aimed to develop hybrid antitumor compounds by synthesizing and characterizing novel N -substituted acrididine-1,8-dione derivatives, designed as hybrids of phthalimide and acridine-1,8-diones. We employed a three-step synthetic strategy and characterized all compounds using IR, 1 H NMR, 13 C NMR, and LC–MS. The cytotoxicity and antitumor activity of five compounds ( 8c , 8f , 8h , 8i , and 8L ) against four cancer cell lines (H460, A431, A549, and MDA-MB-231) compared to human skin fibroblast cells were evaluated. Among the synthesized compounds, compound 8f showed promising activity against skin and lung cancers, with favorable IC 50 values and selectivity index. The relative changes in mRNA expression levels of four key genes (p53, TOP2B, p38, and EGFR) in A431 cells treated with the five synthesized compounds ( 8c , 8f , 8h , 8i , and 8L ) were also investigated. Additionally, molecular docking studies revealed that compound 8f exhibited high binding affinity with TOP2B, p38, p53, and EGFR, suggesting its potential as a targeted anticancer therapy. The results obtained indicate that N -substituted acrididine-1,8-dione derivatives have the potential to be developed as novel antitumor agents with a dual mechanism of action, and compound 8f is a promising candidate for further investigation.
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DOI: 10.1038/s41598-023-41970-0
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