State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
Chem Biodivers. 2024 Apr;21(4):e202301979. doi: 10.1002/cbdv.202301979. Epub 2024 Mar 12.
Acetyl-11-keto-β-boswellic acid (AKBA) is known to inhibit the growth of glioblastoma (GBM) cells and subcutaneous GBM. A series of acetyl-11-keto-β-boswellic acid (AKBA) derivatives containing the oxime-ester functionality or amide side chains were synthesized, and their anti-GBM activities were evaluated. Some of these compounds exhibited significant inhibitory activity against cell proliferation in U87 and U251 GBM cell lines, with IC values in the micromolar concentration range. Cellular thermal shift analysis showed that A-01 and A-10 improved the thermal stability of FOXM1, indicating that these highly active compounds may directly bind to FOXM1 in cells. Docking studies of the two most active compounds, A-01 and A-10, revealed key interactions between these compounds and the active site of FOXM1, in which the amide moiety at the C-24 position was essential for improving the activity. These results suggested that A-10 is a suitable lead molecule for the development of FOXM1 inhibitors. Thus, the rational design of AKBA derivatives with amide side chains holds significant potential for discovering of a new class of triterpenoids capable of inhibiting GBM cell proliferation.
乙酰-11-酮-β-乳香酸（AKBA）已知能抑制神经胶质瘤（GBM）细胞和皮下 GBM 的生长。合成了一系列含有肟酯官能团或酰胺侧链的乙酰-11-酮-β-乳香酸（AKBA）衍生物，并评估了它们对 GBM 的活性。这些化合物中的一些对 U87 和 U251 GBM 细胞系的细胞增殖具有显著的抑制活性，IC 值在微摩尔浓度范围内。细胞热转移分析表明 A-01 和 A-10 提高了 FOXM1 的热稳定性，表明这些高活性化合物可能直接与细胞中的 FOXM1 结合。对两种最活跃的化合物 A-01 和 A-10 的对接研究表明，这些化合物与 FOXM1 的活性位点之间存在关键相互作用，其中 C-24 位的酰胺部分对于提高活性至关重要。这些结果表明 A-10 是开发 FOXM1 抑制剂的合适先导分子。因此，合理设计具有酰胺侧链的 AKBA 衍生物为发现能够抑制 GBM 细胞增殖的新型三萜类化合物具有重要意义。
