An insight into the anticancer potential of sulfonated styrylquinazolines as multifunctional agents targeting...

Developing new microtubule-targeting agents is extremely important for cancer treatment. One of the goals is to overcome drug resistance, since these agents can cause mitotic arrest and thus cause impairment to cell signaling. Despite this, there are many gaps in our understanding of the complex actions of such agents. In this study, we report the synthesis and biological evaluation of a novel series of sulfonic styrylquinazoline derivatives, featuring three quinazoline core variants: unsubstituted, 6-chloro, and 7-chloro. Antiproliferative assays revealed that the 6-chloro derivative exhibited potent sub-micromolar activity against glioblastoma (GBM) and leukemia cell lines, while the 7-chloro analogs showed selective activity against leukemia cells. Importantly, the compounds were selective against normal cells. Further detailed molecular studies revealed that the most active compounds caused cell cycle arrest in the G2/M phase and disrupted microtubule polymerization-depolymerization dynamics, thereby affecting intracellular signaling pathways. Mechanistic studies showed the influence of the derivatives on cell cycle-related proteins (Aurora A and cyclin B1) and the inhibition of EGFR/Akt/mTOR and EGFR/Ras cell signaling. Cell death was induced primarily through apoptosis and potentially via autophagy, depending on the type of cell line. In addition, detailed computational studies have established a plausible binding model for these derivatives at the cevipabulin site of tubulin. Finally, physicochemical properties were determined to ensure adequate bioavailability, also toxicity and therapeutic efficacy were studied on an in vivo model. Notably, the 6-Cl derivative showed significantly better therapeutic efficacy than osimertinib on the zebrafish GBM xenograft model.