Berberine (BBR) exhibits diverse bioactivities, including anticancer activity; but its poor druggability limits its applications. In this study, we designed and synthesized a series of 9-O position modified BBR derivatives aiming to improve its cell permeability and anticancer activity, utilizing a long alkyl chain branched by hydroxyl group and methoxycarbonyl group. Among these compounds, B10 showed 3.6-fold higher intracellular concentration than BBR, as well as 60-fold increased anti-proliferation activity against human lung cancer A549 cells compared with BBR. Treatment with B10 (1, 2 μM) induced apoptosis of A549 cells. Further investigations showed that B10 treatment dose-dependently affected mitochondrial functions, including oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and the morphology of mitochondria in A549 cells. Therefore, this work offers a new way for BBR structural modification through improving cell membrane permeability to affect mitochondrial functions and potential anti-tumor therapy in the future.

小檗碱 (BBR) 具有多种生物活性，包括抗癌活性；但其较差的成药性限制了其应用。在这项研究中，我们设计并合成了一系列 9-O 位修饰的 BBR 衍生物，旨在提高其细胞通透性和抗癌活性，利用羟基和甲氧羰基支化的长烷基链。在这些化合物中，B10的细胞内浓度比 BBR 高 3.6 倍，对人肺癌 A549 细胞的抗增殖活性比 BBR 高 60 倍。用B10 (1, 2 μM) 处理诱导 A549 细胞凋亡。进一步调查表明，B10处理剂量依赖性地影响线粒体功能，包括耗氧率 (OCR)、线粒体膜电位 (MMP) 和 A549 细胞中线粒体的形态。因此，这项工作通过提高细胞膜通透性影响线粒体功能和未来潜在的抗肿瘤治疗为BBR结构修饰提供了新途径。