Improved anti-breast cancer activity through structural modification of fused pyran derivatives and mechanistic investigations

Abstract

Novel fused pyran derivatives were synthesized and evaluated for anticancer activity against MCF7 (ATCC – HTB-22, breast), A549 (ATCC – CCL-185, lung), and HCT116 (ATCC – CCL-247, colorectal) cancer cell lines. Most compounds exhibited broad-spectrum activity. Among them, imidazole-containing derivatives 8a and 8b demonstrated potent anti-breast cancer activity with IC₅₀ values of 8.24 ± 0.19 μM and 4.22 ± 0.81 μM, respectively. Both compounds were nontoxic to MCR5 (ATCC – CCL-171, human diploid fibroblast) cell line. In vitro studies using MCF7 cells showed that 8a and 8b significantly reduced colony formation and inhibited spheroid progression. Cell cycle analysis revealed G1 arrest, a mechanism distinct from the standard drug etoposide. Furthermore, these compounds induced persistent DNA damage and both early and late apoptosis. In addition, ex ovo CAM assay revealed a significant reduction in new blood vessel formation over time compared to untreated controls. Network pharmacology identified EGFR, SRC, and GSK3B as potential targets, and molecular docking studies confirmed strong binding affinities to these proteins. This interaction is proposed to inhibit uncontrolled breast cancer cell growth. Additionally, the compounds exhibited favorable pharmacokinetic properties in silico. These findings suggest that novel fused pyran derivatives, particularly 8a and 8b, are promising candidates for further preclinical development as breast cancer therapeutics.