Transformation of Santonin to a Naproxen Analogue with Anti-Inflammatory Activity

Abstract

Santonin, a natural product, was aromatized with molecular iodine as the catalyst. The new compound was characterized as (S)-methyl-2-(7-hydroxy-5,8-dimethylnaphthalen-2-yl) propanoate (2) based on 2D NMR spectroscopic data. Structurally, compound 2 was highly similar to the anti-inflammatory drug naproxen. The new naproxen analogue had significant potency against cyclooxygenase 1 and 2 (IC50 = 31.0 and 66.1 μM, respectively).

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

“…The use of molecular iodine to accomplish aromatization of sesquiterpene lactones, with subsequent lactone hydrolysis, has been reported before, for example, santonin [15], ionone [39], and perillaldehyde [40]. In the current report, we show that aromatization and lactone opening of vulgarin using molecular iodine as a catalyst yields two derivatives (1 and 2) that are naproxen analogs.…”

“…The reaction was run in a mixture of toluene-MeOH (9:1). This mixture has been reported to be the most efficient one for such a reaction [15]. Moreover, one equivalent of iodine was used, since it has previously been reported to be the optimum quantity [15].…”

“…This mixture has been reported to be the most efficient one for such a reaction [15]. Moreover, one equivalent of iodine was used, since it has previously been reported to be the optimum quantity [15]. Since iodine also catalyzes esterification, the used methanol yielded the methyl ester derivatives of the two compounds (1 and 2) rather than the free acids.…”

“…Sesquiterpene lactones are one of the major and attractive bioactive classes due to their complex structures with a wide range of biological activities such as cytotoxic, anti-inflammatory, and antiviral properties [2][3][4][5][6][7][8][9][10][11][12][13]. Because of their structural complexity and biodiversity, they are potential scaffolds for the development of new bioactive compounds [14][15][16]. The eudesmanolide sesquiterpene vulgarin has been reported to occur in numerous Artemisia species, including A. vulgaris L., after which it was named [17,18].…”