Late‐stage functionalization (LSF) aids drug discovery efforts by introducing functional groups onto C−H bonds on pre‐existing skeletons. We adopted the LSF strategy to synthesize analogues of the abundantly available triterpenoid, glycyrrhetinic acid (GA), by introducing aryl groups in the A‐ring, expanding the A‐ring and selectively activating one methyl group of the gem‐dimethyl groups. Intriguingly, two compounds were found to preferentially accumulate in the mitochondrial compartment of MDA‐MB‐231 breast cancer cells, to cause depolarization of mitochondrial membrane potential and to induce antiproliferative and anti‐invasive effects through enhanced mitochondrial superoxide production with parallel depletion of GSH levels. Furthermore, intraperitoneal administration of these two compounds, in comparison with GA, greatly regressed breast tumor growth and metastasis in a SCID mouse model bearing labeled MDA‐MB‐231 cells.

中文翻译：

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sp3 - 使用晚期功能化作为潜在乳腺肿瘤消退剂的富含甘草次酸类似物。

后期功能化 (LSF) 通过将官能团引入到预先存在的骨架上的 C-H 键上来帮助药物发现工作。我们采用 LSF 策略通过在 A 环中引入芳基、扩大 A 环和选择性激活宝石的一个甲基来合成大量可用的三萜类化合物甘草次酸 (GA) 的类似物-二甲基。有趣的是，发现两种化合物优先积聚在 MDA-MB-231 乳腺癌细胞的线粒体区室中，导致线粒体膜电位的去极化，并通过增加线粒体超氧化物的产生与 GSH 水平的平行消耗来诱导抗增殖和抗侵袭作用. 此外，与 GA 相比，这两种化合物的腹腔给药大大降低了带有标记的 MDA-MB-231 细胞的 SCID 小鼠模型中的乳腺肿瘤生长和转移。