An Seungchan, Chun Jaemoo, Lee Joohee, Kim Yeong Shik, Noh Minsoo, Ko Hyejin
College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea.
Biomol Ther (Seoul). 2024 Sep 1;32(5):627-634. doi: 10.4062/biomolther.2023.210. Epub 2024 Aug 2.
Sesquiterpene lactones, a class of natural compounds abundant in the Asteraceae family, have gained attention owing to their diverse biological activities, and particularly their anti-proliferative effects on human cancer cells. In this study, we systematically investigated the structure-activity relationship of ten sesquiterpene lactones with the aim of elucidating the structural determinants for the STAT3 inhibition governing their anti-proliferative effects. Our findings revealed a significant correlation between the STAT3 inhibitory activity and the anti-proliferative effects of sesquiterpene lactones in MDA-MB-231 breast cancer cell lines. Among the compounds tested, alantolactone and isoalantolactone emerged as the most potent STAT3 inhibitors, highlighting their potential as candidates for anticancer drug development. Through protein-ligand docking studies, we revealed the structural basis of STAT3 inhibition by sesquiterpene lactones, emphasizing the critical role of hydrogen-bonding interactions with key residues, including Arg609, Ser611, Glu612, and Ser613, in the SH2 domain of STAT3. Furthermore, our conformational analysis revealed the decisive role of the torsion angle within the geometry-optimized structures of sesquiterpene lactones in their STAT3 inhibitory activity (=0.80, <0.01). These findings not only provide preclinical evidence for sesquiterpene lactones as promising phytomedicines against diseases associated with abnormal STAT3 activation, but also highlight the importance of stereochemical aspects in their activity.
倍半萜内酯是一类在菊科植物中大量存在的天然化合物，因其多样的生物活性，尤其是对人类癌细胞的抗增殖作用而受到关注。在本研究中，我们系统地研究了十种倍半萜内酯的构效关系，旨在阐明其抑制信号转导和转录激活因子3（STAT3）从而发挥抗增殖作用的结构决定因素。我们的研究结果表明，在MDA-MB-231乳腺癌细胞系中，倍半萜内酯的STAT3抑制活性与其抗增殖作用之间存在显著相关性。在所测试的化合物中，土木香内酯和异土木香内酯是最有效的STAT3抑制剂，突出了它们作为抗癌药物开发候选物的潜力。通过蛋白质-配体对接研究，我们揭示了倍半萜内酯抑制STAT3的结构基础，强调了与STAT3的SH2结构域中的关键残基（包括Arg609、Ser611、Glu612和Ser613）形成氢键相互作用的关键作用。此外，我们的构象分析揭示了倍半萜内酯几何优化结构中的扭转角在其STAT3抑制活性中的决定性作用（=0.80，<0.01）。这些发现不仅为倍半萜内酯作为对抗与STAT3异常激活相关疾病的有前景的植物药提供了临床前证据，也突出了立体化学方面在其活性中的重要性。
