Investigating the multi-mechanistic anticancer effects of 4-bisarylurea thiouracil derivatives in breast cancer cells

The study reports the synthesis of a series of 4-bisarylureathiouracil derivatives (6a-e) for potential use in breast cancer treatment. In vitro cytotoxicity was assessed in MCF-7 and MDA-MB-231 human breast cancer cell lines, revealing significant anti-cancer activity. Compound 6e exhibited the highest cytotoxicity, with IC₅₀ values of 7.94 μM for MCF-7 and 6.67 μM for MDA-MB-231, although it was also the most toxic to RAW 264.7 macrophage cells. In contrast, compound 6c demonstrated strong efficacy against both cancer cell lines (IC₅₀ = 9.23 ± 0.6 μM for MCF-7 and 7.72 ± 0.6 μM for MDA-MB-231) while maintaining selectivity (SI values >10.8 and > 12.9, respectively). Flow cytometry and caspase-3 assays indicated that compounds 6a-c induced apoptosis in MCF-7 cells. In anti-inflammatory assays, compounds 6a and 6d showed significant effects, while 6c demonstrated the weakest, suggesting its cytotoxicity is not linked to anti-inflammatory properties. Compound 6c was prioritised for further investigation because of its preferential targeting of cancer cells. Proteomic analysis of 6c-treated cells revealed significant dysregulation of apoptosis, angiogenesis and VEGF signalling, Rho signal transduction, and pi3k-akt signalling pathways. These findings highlighted the potential of compounds 6a-e as effective anticancer agents, warranting further investigation and optimization for therapeutic applications.