From natural product to anticancer agents: Semi-synthesis, biological evaluation, and molecular docking studies of novel β-Himachelene-Based triazole hybrids

A novel series of β-Himachelene-based aromatic ester–1,4-disubstituted-1,2,3-triazole hybrids was efficiently synthesized via a regioselective copper-catalyzed azide–alkyne cycloaddition (CuAAC). The semi-synthesized compounds were fully characterized using ¹H NMR, ¹³C NMR, FT-IR, and HRMS analyses. Their in vitro cytotoxicity was evaluated against four cancer cell lines: HT-1080 fibrosarcoma, A-549 lung carcinoma, and MCF-7 and MDA-MB-231 breast carcinoma. Most of the tested compounds exhibited moderate to significant activity, with IC₅₀ values ranging from 8.06 to 47 µM. Notably, compound 3d, bearing a 4-methoxy substituent, showed the highest potency against HT-1080 and MCF-7 cells. Mechanistic studies revealed that 3d induced apoptosis via caspase-3/7 activation and caused cell cycle arrest at the G₀/G₁ phase. Complementary molecular docking studies demonstrated strong binding affinity of 3d to caspase-3/7, highlighting tight ligand–receptor interactions. These results indicate that compound 3d represents a promising β-Himachelene-derived anticancer candidate for further in vivo evaluation.