Wang Cai Yi, Qin Feng, Wang Chun-Gu, Kim Donghwa, Li Jin-Jun, Chen Xian-Lan, Wang Heng-Shan, Lee Sang Kook
Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
Bioorg Chem. 2023 May;134:106445. doi: 10.1016/j.bioorg.2023.106445. Epub 2023 Feb 26.
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.
从两面针中分离出7种以前未描述过的具有不同构型和不寻常异戊烯基取代的四氢呋喃木脂素，即亮叶木脂素D-J（分别对应化合物1、2、4、6、7、9和10），以及14种已知木脂素。值得注意的是，化合物4是一种罕见的天然呋喃核心木脂素，由四氢呋喃芳构化衍生而来。测定了分离出的化合物（1-21）在各种人类癌细胞系中的抗增殖活性。构效关系研究表明，木脂素的空间定位和手性对其活性和选择性有重要影响。特别是，化合物3（芝麻素酮）在癌细胞中表现出强大的抗增殖活性，包括对奥希替尼耐药的非小细胞肺癌（HCC827-osi）细胞。化合物3还抑制了HCC827-osi细胞的集落形成并诱导其凋亡死亡。潜在的分子机制表明，3下调了HCC827-osi细胞中c-Met/JAK1/STAT3和PI3K/AKT/mTOR信号通路的激活。此外，3与奥希替尼联合使用对HCC827-osi细胞的抗增殖活性具有协同作用。总体而言，这些发现为从两面针中分离出的新型木脂素的结构解析提供了信息，芝麻素酮被确定为对奥希替尼耐药肺癌细胞具有抗增殖作用的潜在化合物。
