Artemisianins A-D, new stereoisomers of seco-guaianolide involved heterodimeric [4+2] adducts from Artemisia argyi induce apoptosis via enhancement of endoplasmic reticulum stress

Artemisianins A-D (1–4), four stereoisomers of sesquiterpenoid dimers, forming via [4+2] cycloaddition from a 1, 10-seco-guaianolide dienophile and a guaianolide diene, along with two biosynthetically related precurors 5 and 6, were isolated from the famous traditional Chinese medicine Artemisia argyi. The structures of 1–4, including their absolute configurations, were elucidated by extensive spectroscopic data and ECD/TDDFT calculation analysis. Compounds 1–4 exhibited cytotoxicity with IC50 values ranging from 7.2 to 23.3 μM. The accumulation of Ca2+ in cytoplasm and enlarged endoplasmic reticulum (ER) indicated that 1 mediated HT-29 cancer cell apoptosis through improvement of ER-stress, which was further proved by unfolded protein response (UPR) pathway on basis of the upregulation of IRE1α, p-PERK, ATF6, and CHOP.