Spiroethers comprise a sub-class of spirocycles and exert various biological properties such as antibacterial and anti-tumor activities. The present study investigated the total spiroether isomers present inmethanolic extract of root and aerial parts of 40 Arnebia species collected from 20 different geographical zones in Iran. Also, the cytotoxic effects of the methanolic extract of the samples and the retrieved isomers were assessed against eight cancerous and one non-cancerous cell-lines. In all Arnebia samples tested, two spiroether isomers namely, cis- (E)- and trans-(Z)-spiroethers were found and it was observed that root and aerial parts of Arnebia euchroma had significantly high levels of the two isomers as determined by High Performance Liquid Chromatography coupled with Photodiode Array Detection-Mass Spectrometry (HPLC-PAD-MS). Both isolated compounds, particularly cis-(E)-spiroether, could inhibit cancer cells proliferation while had little destructive effects in normal cells. Cis-(E)- and trans-(Z)-spiroethers inhibited HepG2 cell line proliferation with IC50 values of 3.23 § 0.24 and 4.80 § 0.15 mg/mL, respectively. Among the samples extracts, aerial parts and root extracts of A. euchroma had the highest anti-cancer activity against HepG2 with IC50 values of 6.32 § 0.23 and 7.50 § 0.11 mg/mL, respectively. The present study showed variations in cytotoxic activity of cis-(E)- and trans-(Z)-spiroethers among Arnebia species.

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