Title : Design, hemisynthesis, and anticancer evaluation of totarol-oxazole derivatives derived from Tetraclinis articulata
Abstract:
Oxazole derivatives are important motifs in medicinal chemistry due to their broad biological versatility. In the present study, totarol, a bioactive diterpenoid isolated from Tetraclinis articulata (thuya) wood sawdust, was used as a natural scaffold for the design of novel oxazole-based derivatives. A series of totarol–oxazole derivatives was hemisynthesized via selective functionalization of the phenolic group of totarol, followed by cyclization reactions leading to the formation of the oxazole ring. Structural elucidation was achieved using a combination of NMR spectroscopy, FT- IR, HRMS, and single-crystal X-ray diffraction, confirming the chemical structures and providing detailed insights into stereochemistry and molecular geometry. Density functional theory (DFT) calculations were performed to investigate electronic properties, frontier molecular orbitals, and reactivity descriptors, while molecular docking studies were carried out to explore potential binding interactions with molecular targets associated with fibrosarcoma HT-1080 cells. In vitro cytotoxicity evaluation revealed that several oxazole derivatives exhibited significant antiproliferative activity, showing improved efficacy compared to the parent totarol. The consistency between experimental results and computational predictions highlights the relevance of oxazole functionalization in enhancing anticancer activity. Overall, these findings support totarol–oxazole derivatives derived from Tetraclinis articulata as promising anticancer agents, providing a solid foundation for further structural optimization and mechanistic investigations.
Keywords: Totarol, Tetraclinis articulata, Oxazole, X-ray crystallography, DFT, Molecular docking, HT-1080
