Novel Vulgarin Derivatives: Chemical Transformation, In Silico and In Vitro Studies

Vulgarin, an eudesmanolide sesquiterpene isolated from Artemisia judaica, was refluxed with iodine to produce two derivatives (1 and 2), which were purified and spectroscopically identified as naproxen methyl ester analogs. The reaction mechanism by which 1 and 2 were formed is explained using a sigmatropic reaction with a 1,3 shift. The scaffold hopping via lactone ring opening enabled the new derivatives of vulgarin (1 and 2) to fit well inside the COX-2 active site with ΔG of -7.73 and -7.58 kcal/mol, respectively, which was better than that of naproxen (ΔG of -7.04 kcal/mol). Moreover, molecular dynamic simulations showed that 1 was able to achieve a faster steady-state equilibrium than naproxen. The novel derivative 1 showed promising cytotoxic activities against HepG-2, HCT-116, MCF-7, and A-549 cancer cell lines compared to those of vulgarin and naproxen.