Novel lignans from Zanthoxylum nitidum and antiproliferation activity of sesaminone in osimertinib-resistant non-small cell lung cancer cells.

[Display omitted] • Seven new tetrahydrofuran lignans with unusual isopentenyl substitutions, along with 14 known ones, were isolated from Zanthoxylum nitidum. • Tetrahydrofuran-core lignan 3 showed higher activity than furan-core lignan 4 in osimertinib-resistant non-small cell lung cancer cells. • Compound 3 suppressed the c-Met/JAK1/STAT3 and PI3K/AKT/mTOR signaling pathway in the HCC827-osi cells. • Osimertinib and 3 exhibited synergistic anticancer effects in HCC827-osi cells, and 3 suppressed STAT3 protein level stronger than osimertinib. Seven previously undescribed tetrahydrofuran lignans with different configurations and unusual isopentenyl substitutions, nitidumlignans D-J (corresponding to compounds 1 , 2 , 4 , 6 , 7 , 9 and 10), along with 14 known lignans, were isolated from Zanthoxylum nitidum. Notably, compound 4 is an uncommon naturally occurring furan-core lignan derived from tetrahydrofuran aromatization. The antiproliferation activity of the isolated compounds (1 – 21) was determined in various human cancer cell lines. The structure–activity study revealed that the steric positioning and chirality of the lignans exert important effects on their activity and selectivity. In particular, compound 3 (sesaminone) exhibited potent antiproliferative activity in cancer cells, including acquired osimertinib-resistant non-small-cell lung cancer (HCC827-osi) cells. Compound 3 also inhibited colony formation and induced the apoptotic death of HCC827-osi cells. The underlying molecular mechanisms revealed that 3 downregulated the activation of the c-Met/JAK1/STAT3 and PI3K/AKT/mTOR signaling pathways in the HCC827-osi cells. In addition, the combination of 3 and osimertinib exhibited synergistic effects on the antiproliferative activity against HCC827-osi cells. Overall, these findings inform the structure elucidation of novel lignans isolated from Z. nitidum, and sesaminone was identified as a potential compound for exerting antiproliferative effects on osimertinib-resistant lung cancer cells. [ABSTRACT FROM AUTHOR]