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 IC₅₀ 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.

中文翻译：

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作为潜在抗 GBM 药物的新型乙酰基-11-酮-β-乳香酸衍生物的合成


乙酰-11-酮-β-乳香酸 (AKBA) 已知可抑制胶质母细胞瘤 (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基-11-酮-β-乳香酸（AKBA）衍生物，并评估了它们的抗GBM活性。其中一些化合物对 U87 和 U251 GBM 细胞系中的细胞增殖表现出显着的抑制活性，IC ₅₀值在微摩尔浓度范围内。细胞热位移分析表明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内的FOXM1结合。对两种最活跃的化合物A-01和A-10的对接研究揭示了这些化合物与 FOXM1 活性位点之间的关键相互作用，其中 C-24 位点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衍生物对于发现一类能够抑制GBM细胞增殖的新型三萜类化合物具有巨大的潜力。